Methods, agents, and devices for local neuromodulation of autonomic nerves

ABSTRACT

Methods, agents, and devices to treat medical conditions through local chemical neuromodulation of the autonomic nervous system are described. Drug formulations may be injected at or near ganglia, nerve plexi, ganglionated plexi, and nerves to treat different diseases. Target sites for the treatment of cardiac and other disease conditions may include extrinsic stellate (cervicothoracic) and cervical ganglia of the sympathetic chain, and intrinsic cardiac nerves and ganglionated plexi innervating the myocardium.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. provisional application No.62/293,327, filed Feb. 9, 2016, which is hereby incorporated byreference in its entirety.

BACKGROUND

There is increasing experimental and clinical evidence that theautonomic regulation is essential to maintain normal physiologicfunction and response in organs and autonomic dysfunction plays asignificant role in the development of chronic diseases. Abnormalitiesin the sympathetic and parasympathetic branches of the autonomic nervoussystem have been shown to be associated with several medical conditionsincluding, hypertension, cardiac disease (angina, myocardial infarction,atrial and ventricular arrhythmias, cardiac arrest, sudden cardiacdeath, and heart failure, channelopathies), pulmonary hypertension,sleep apnea, chronic kidney disease, metabolic syndrome (obesity,glucose metabolism and insulin sensitivity), chronic obstructivepulmonary disease (COPD), stroke, pain, glaucoma (and other oculardiseases), hyperhidrosis, gut disease (Crohn's disease, irritable bowelsyndrome), and polycystic ovary syndrome.

A majority of these diseases are currently treated by systemic daily useof oral medications, some of which may not specifically target theautonomic nervous system or sympathetic nerves. Drugs have side effectsand some patients are not responsive to drug therapy. Moreover, patientsmay not be compliant daily medication limiting the effectiveness oftreatment.

A few device-based therapies are currently available or are underclinical investigation to treat different disease states. Implantablecardioverting defibrillators (ICDs) and pace makers are used to treatcardiac arrhythmias through electrical energy stimulation of at nerveconduction sites in the heart. Implantable neurostimulation devicesactivate the vagus nerve, spinal cord, and carotid body (orbaroreceptors), to affect the autonomic function, are in clinical use ordevelopment to treat hypertension, heart failure, and chronic pain.Implant-based treatments are invasive and require the implantation of anexpensive electrical generator and electrical leads to continuouslymonitor nerve signals and stimulate the nerves. Tissue-ablationcatheters, based on radiofrequency (RF), ultrasound, and cryothermalenergy forms, are in development or clinical use to treat cardiacarrhythmias, hypertension, pulmonary hypertension, and COPD by ablatingtissue near specific organs. Ablation treatments may cause collateraldamage to surrounding tissue and their long-term efficacy could beimproved.

Local chemical neuromodulation methods that overcome these limitationsare described. Target nerve, ganglion, and nerve plexus sites inside thebody, that mediate chronic diseases are described. Methods to access andverify nerve location, affect nerve function, and treat diseases aredescribed. Treatments may include a one-time administration of aneuromodulating or nerve-affecting drug composition, locally, at or nearneuronal tissue sites (neurons, ganglia, plexi, and combinations). Drugcompositions and formulations are also described.

SUMMARY

Methods are described for treating disease by inserting a therapydelivery device inside the body, advancing the device to a nerve site ofthe autonomic nervous system, measuring the nerve activity at the targetsite, and administering a small volume of drug formulation, locally, ator near the target nerve site to affect nerve function and treat thedisease.

Nerve sites may include the cervicothoracic ganglion, also known as thestellate ganglion, adjacent cervical and thoracic ganglia (C1 to T4) ofthe sympathetic chain, interconnecting nerves between them, and ramicommunicantes. Other diseases and organ-specific nerve sites and gangliaare also described.

Medical conditions treated may include cardiac disease condition likeangina, myocardial infarction (acute and late), atrial arrhythmias(fibrillation), ventricular arrhythmias (ventricular fibrillation,ventricular tachycardia), heart failure, channelopathies (long-QTsyndrome, polymorphic ventricular tachycardia), cardiomyopathy, cardiacarrest, and sudden cardiac death. Other disease conditions that may betreated include stroke, hypertension, pulmonary hypertension, pain,chronic regional pain syndrome, post-traumatic stress syndrome, and hotflashes.

Agents may include drug formulations based on ion pump and ion channelantagonists, G-protein coupled receptor (GPCR) agonists and antagonists,etc. Drug formulations may be administered at or near target nerves organglia directly, or may be mixed with excipients and polymers toprovide sustained drug release over time to permanently affect nervefunction and treat the disease for several days to several years.

Neuromodulatory effects of drug compositions described may includeblocking nerves (to stop nerve signal transmission), upregulating nerves(to increase sympathetic nerve activity), and downregulating nerves (toreduce parasympathetic nerve activity) over short or long periods oftime. Drug compositions are described which may treat disease bypermanently killing nerves through apoptosis and preventing nerveregeneration, while reducing damage to surrounding organs and tissue.

Also described are methods and devices for accessing ganglia, plexi,ganglionated plexi, sympathetic nerves and nerve fibers inside the body;for visualizing and measuring autonomic activity at target nerve sitesbefore treatment; for locally administering drug formulations at or nearnerve target sites and treat disease; and for monitoring autonomicfeedback during and after treatment.

Methods are described to identify, screen, and qualify patients withchronic diseases mediated by autonomic dysfunction. Devices and methodsare described to monitor nerve activity and other diagnostic markers toverify disease mechanisms and target nerve locations for disease.

Treatments described may be used either as an adjunctive treatment or analternative treatment to other therapies in clinical practice or underclinical investigation. Treatments described may be administered at thetime of primary procedure. Treatment may also be performed, 3 weeks to 3months, prior to a second procedure to allow sufficient time forreduction in catecholamine levels.

Drug formulations described may be injected at one or more target nervelocations inside the body to treat one medical condition. Drugformulations, administered at different sites, may be different toachieve desired therapeutic benefits at specific locations over desiredtime periods.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows the autonomic nervous system, including the sympatheticand parasympathetic nervous system and the sympathetic chain ganglia,innervating various organs in the body; FIGS. 1B-1D show pathways of thegrey and white rami communicantes connecting the spinal nerves and thesympathetic nervous system near the dorsal root ganglia; FIGS. 1E and 1Fshow the post-ganglionic extrinsic cardiac sympathetic nerves andintrinsic ganglionated plexi innervating the heart.

FIG. 2A shows the anatomy of the stellate ganglion, ganglia of thesympathetic chain, and nearby tissue and vascular structures in theneck; FIG. 2B shows the skeletal structure and blood vessels surroundingthe stellate ganglion, which may be used for surgical and for vascularaccess; FIG. 2C shows the intercostal arteries and intercostal veinsadjacent to the thoracic sympathetic chain and ganglia (sympathetictrunk) in relation to the ribs and heart inside the thoracic cavity.

FIG. 3A shows the ANS interactions between the brain and the heart(mechanism of action) for the development of cardiac arrhythmias at themacroscopic level; FIG. 3B shows the various sympathetic andparasympathetic nerve pathways involved with ANS dysfunction, nervetarget sites for treatment, and mechanism of action at themicroscopic/cellular level in the stellate ganglion and cardiac nervesin the heart.

DESCRIPTION

Methods, agents, and devices are described to treat diseases and medicalconditions through local chemical neuromodulation at or near nervetarget sites inside of the autonomic nervous system, such as thesympathetic nerves, ganglia, and nerve plexi inside the body.

Anatomy of the Autonomic Nervous System and the Sympathetic Chain

The autonomic nervous system (ANS) is the division of the peripheralnervous system that acts as a control system to influence internalorgans and unconsciously regulate bodily functions, such as heart rate,digestion, and respiration rate etc., as shown in FIG. 1A. The ANS hastwo divisions, the sympathetic nervous system (SNS) and theparasympathetic nervous system (PSNS). The SNS is considered the “fightor flight” system and the PSNS is considered the “rest and digest”system. In most cases, sympathetic and parasympathetic nervous systemshave opposing actions of activating and inhibiting a physiologicalresponse and form feedback loops within various organs and systemsinside the body. The functions of the ANS may be further divided intosensory (afferent, sending signals to the brain and central nervoussystem) and motor (efferent, affecting end organs) subsystems.

Sympathetic Nervous System:

The SNS includes nerve cells with bodies in a column along either side(left and right) of the vertebral bodies from the T1 to L2/3 vertebrae.These cell bodies are general viscerent efferent, preganglionic neuronsand they can synapse with their postganglionic neurons at severallocations—paravertebral ganglia, prevertebral ganglia and chromaffincells. As shown in FIG. 1A, the paravertebral ganglia of the sympatheticchain include cervical ganglia, thoracic ganglia, lumbar ganglia, andsacral ganglia linked together on each side of the human body, alsoreferred to as the sympathetic trunks.

The cervical ganglia are paravertebral ganglia of the SNS and includethe superior-cervical ganglion adjacent to C2 and C3 (innervating theheart, head and neck), middle cervical ganglion (adjacent to C6)innervating the heart and the neck, and the inferior cervical ganglion(adjacent to C7). The inferior cervical ganglion is often fused to thefirst thoracic ganglion to form a single structure, called the stellateganglion or cervicothoracic ganglion, innervating the heart, lower neck,arm, and posterior cranial arteries. The thoracic ganglia are 12paravertebral ganglia. Thoracic (cardiopulmonary, the greater, lesserand least) splanchnic nerves emerging from the ganglia innervate theabdominal structures. The lumbar ganglia, typically four, areparavertebral ganglia. Lumbar splanchnic nerves arise from these gangliaand supply sympathetic efferent nerve fibers to nearby plexi—the celiacplexus, superior mesenteric plexus, inferior mesenteric plexus, renalplexus, and aortic plexus. The sacral ganglia are paravertebral gangliaof sympathetic trunk. Generally there are 4-5 sacral ganglia providesympathetic nerve fibers to the sacral splanchnic nerves to join thehypogastric plexus.

The sympathetic truck connects with the spinal nerves through structurescalled rami communicantes, as shown in FIGS. 1B-1D. A ramus communicansis a connecting nerve branch between a spinal nerve and the sympathetictrunk. Two kinds of rami communicantes, white and grey, are responsiblefor conveying ANS signals, specifically for the SNS. Grey ramicommunicantes are more myelinated that white rami and exist at everylevel of the spinal cord. They are responsible for carryingpost-ganglionic nerve fibers from the paravertebral ganglia to theirdestination, and for carrying the pre-ganglionic fibers, which enter theparavertebral ganglia but do not synapse. White rami communicantes areonly present near the intermediolateral cell column (T1-L2) and areresponsible for carrying pre-ganglionic nerve fibers from the spinalcord to the paravertebral ganglia.

The prevertebral ganglia are sympathetic ganglia that lie between theparavertebral ganglia and the target organ. They consist of the celiacganglion, aortico-renal ganglion, superior mesenteric ganglion andinferior mesenteric ganglion. Post-ganglionic neurons that synapse inthese ganglia innervate the pelvic viscera through different (greater-T5to T9; lesser-T10-T11; and least-T12) splanchnic nerves, including theenteric nervous system, kidneys, bladder and other organs present in theabdomen.

Parasympathetic Nervous System:

The PSNS consists of nerve cells with preganglionic bodies in brain stem(cranial nerves II, VII, IX, X) and the spinal cord (S2, S3 and S4).They synapse with post-ganglionic neurons near the parasympatheticganglia of the head (ciliary, submandibular, pterygopalatine and oticganglia) or near the organ wall innervated by the vagus or sacralnerves. Post-ganglionic parasympathetic splanchnic nerves and the vagusnerve innervate the organs such as the heart, lungs, liver and stomach.Vagal efferents extend from the medulla to post-ganglionic nerves thatinnervate the atria in the heart.

Neurotransmitters:

Norepinephrine (NE) is the primary neurotransmitter in post-ganglionicnerves of the SNS and acetylcholine (ACh) the neurotransmitter inpre-ganglionic nerves responsible for nerve function, signal conduction,sensory perception and motor function. Sympathetic nerve fibers thatsecrete NE are also called adrenergic fibers. Dopamine, nitric oxide,neuropeptide Y, vasoactive intestinal peptide, and adenosine may alsoplay a role depending on the nerve location, type and disease state.Acetylcholine is the chief neurotransmitter of the PSNS, and acts onmuscarinic and nicotinic cholinergic receptors. Parasympathetic nervefibers that secrete ACh are referred to as cholinergic fibers.

General Role of ANS and Nerve Targets:

Experimental and clinical evidence shows that the autonomic nervoussystem, and more specifically the SNS, plays an important role in thepathogenesis of many diseases. Aberrant afferent signaling from organreceptors to the CNS can reflexively cause excessive efferent activityto specific target organs resulting in organ remodeling and diseaseprogression. Such effects of excessive efferent and afferent activitymay not be systemic throughout the body and may be localized to specificorgans. Treating target sites within the body may reduce efferent andafferent SNS overactivity and restore autonomic balance.

For example, there is considerable evidence that essential hypertensionis neurogenic and is initiated and by SNS overactivity. Variousmechanisms have been proposed. They include the increased centralsympathetic outflow, reduced local neurotransmitter (or catecholamine,norepinephrine) reuptake into neurons, lower arterial baroreflexsensitivity, and sympathetic neuromodulation by angiotensin II. Amongthese, reports by Schlaich et al., show that increased rates ofsympathetic nerve firing and reduced neuronal NE reuptake are the majorcontributors for sympathetic overactivation; the role of angiotensin IIand baroreflex restraint II are minimal. Hypertensive patients hadhigher nerve firing rated (increased muscle sympathetic nerve activity)and elevated total systemic, cardiac, and renal NE spillover levels.Their cardiac neuronal NE reuptake was also lower compared tonormotensive subjects. In addition, the older patients showed greaterneurogenic (neurotransmitter level) sensitivity to stress factors (likephysical exercise, hypoglycemia or upright posture) compared to theyoung. The higher plasma NE levels, from enhanced SNA andneurotransmitter release, compensate for decreased functional responseof the target organ to adrenergic stimulation, and cause organ damageand disease. Similar detrimental SNA overactivity, higher levels ofneurotransmitters and resultant cellular remodeling is observed in otherorgans and organ tissue, and contribute to various medical conditionsand chronic diseases.

Oral medication is the primary treatment for a many chronic diseases.Pharmacologic treatments for reducing SNS overactivity are not targetedto specific organs, organ systems; nerves nerve endings or physiologicalchanges and produce a global reduction in SNA or systemic reduction incatecholamine or neurotransmitter levels. Such treatments may beinappropriate for non-target organs and organ systems and may not beeffective where the disease mechanism is mediated by local activationand transport of neurotransmitters at specific nerve sites. Thus,targeting autonomic nerves innervating organs, at locations inside thebody, may be more desirable to treat chronic diseases and improve organfunction, compared to daily use of oral drugs. Drugs often haveundesirable side effects, and patients are not compliant to their dailymedication, both of which are significant problems facing healthcare.Methods are described to overcome these limitations and treat chronicdiseases by local neuromodulation of sympathetic nerves, located in thecervical and thoracic ganglia of the sympathetic chain of the autonomicnervous system, and located within target organs and interconnectingnerve fibers, and through local administration of drug formulations.

Nerve locations inside the body include nerve bundles, nerve fibers ornerve clusters innervating organs, ganglia containing nerve bodies,nerve plexi (nerve junctions), and ganglionated plexi and glial cells.They also include portions of the nerve, including the nucleus, axon,Schwann cells, and the synaptic terminal. Agents may be deliveredlocally to a targeted nerve or portion of a nerve; to a ganglion, aportion of a ganglion or ganglia; to a nerve plexus, a portion of anerve plexus or nerve plexi; to a ganglionated nerve plexus, a portionof a ganglionated nerve plexus or a nerve plexi at different anatomiclocations inside the body. Examples of various disease states or medicalconditions, treatment methods, formulations, and devices are describedbelow.

Cardiac Medical Conditions and Therapies

Cardiac Arrhythmias and Sudden Cardiac Death:

The cardiac nervous system consists of the extrinsic and intrinsicnervous component systems. The extrinsic cardiac nervous system (ECNS)provides sympathetic connections between the myocardium and thecervical, stellate and thoracic ganglia and parasympathetic connectionsbetween the atrial myocardium and the medulla oblongata, as shown inFIGS. 1E and 1F. Sympathetic innervation is provided by the superiorcervical ganglia and the cervicothoracic (stellate) ganglia whichcommunicate with the cervical nerves C1-C3, and with the cervical nervesC7-C8 to the thoracic nerves T1-T2. The thoracic ganglia (as low as atleast the 4th thoracic ganglion) also contribute to the sympatheticinnervation of the heart. The superior, middle, and inferior cardiacnerves from these ganglia innervate the heart by following thebrachiocephalic trunk, common carotid arteries, and subclavian arteries.The thoracic cardiac nerves in the posterior mediastinum follow a morecomplex course to reach the heart in the middle mediastinum.Parasympathetic innervation to the heart is mediated by the vagusnerves. The vagal nerve fibers converge at a distinct fat pad betweenthe superior vena cava and the aorta (known as the ‘third fat pad’) enroute to the sinus and atrioventricular nodes.

The intrinsic cardiac nervous system (ICNS) is composed of a complexneural network of ganglionated plexi (GPs), which are concentratedwithin epicardial fat pads, interconnecting ganglia and axons in theheart (FIG. 1E). It is a network that transduces local cardiac signalsand inputs from central neurons. Other regions that are richlyinnervated by the ICNS and have a high density of major GPs are the fatpads at the left and right pulmonary vein (PV)-atrial junctions and thealong the ligament of Marshall. These pulmonary vein ganglia (PVG) serveas ‘integration centers’ for the right and left vagosympathetic trunksand modulate cardiac rhythm and AF inducibility. In addition to themajor GPs, recent studies have shown there is an extensive atrial neuralnetwork composed of axons and ganglia (containing a small number ofcholinergic, adrenergic, efferent and interconnecting neurons) scatteredthroughout the atrial parenchyma. This network is a peripheral extensionof the intrinsic cardiac autonomic system directly connects with thesino-atrial node (SAN) controls heart rhythm. The sinus node isprimarily innervated by the right-atrial GP, whereas theatrioventricular (AV) node is innervated by the inferior vena cavainferior atrial GP.

The autonomic nervous system plays a major role in the pathophysiologyof arrhythmias, both atrial and ventricular, and sudden cardiac death.Various autonomic pathways and interactions between nerves and organs atthe macroscopic and microscopic level, are shown in FIGS. 3A and 3B,respectively. Therapies and therapeutic targets in development likecarotid body denervation (carotid baroreceptors), cardiac ganglion(vagal nerve stimulation), and renal nerves (renal denervation) are alsoshown in FIG. 3B. Interactions between the brain and heart(neuro-cardiac axis), due to stress, emotion, exercise, metabolism,etc., can alter afferent and efferent cardiac signaling resulting inelectrical and structural dysfunction of the heart. Negatively-chargedemotion can result in sympathetically-mediated coronary ischemia,platelet activation, changes in hemodynamics, and catecholamine (NE)release. Coronary artery disease from atherosclerosis can also block theblood vessels supplying oxygen to the heart, resulting in heart attackor myocardial infarction (MI). Such electrical and mechanicaldisturbances along with inflammation, fibrosis, and genetics, can damagecardiac muscle (scar formation) and reduce the structural performance orpumping efficiency of the heart. Specific role of these electrical,structural, and autonomic remodeling in the development of atrial andventricular arrhythmias is detailed below.

Atrial Arrhythmias:

The ICNS consisting of the major GPs and interconnected neural networkin the atrium contributes to initiation of AF and progression todifferent states of AF-paroxysmal (PAF), persistent and long-standingpersistent AF. Hyperactivity of the ICNS causes the release of excessiveamount of acetylcholine and catecholamines and may lead to rapid firingfrom PVs or non-PV sites. Focal firing from GPs near PV roots (or PVGs)and left atrial appendage (LAA) has been associated with occurrence ofPAF. Five GP anatomic sites known to be associated with AF andaccessible from the left-atrial endocardium are the superior left GP(SLGP), anterior right GP (ARGP), inferior left GP (ILGP), inferiorright GP (IRGP), and Marshall tract GP (MTGP). At the cellular level,the release of adrenergic neurotransmitters (like norepinephrine)mobilizes excess intracellular calcium leading to early afterdepolarizations (EADs), which can trigger ectopic firing of the PVcells. PVGs function as local integration centers between the heart andthe ECNS as well as act independently to affect SAN automaticity andmyocardial contractility functions.

Other (reentrant) forms of AF can also be initiated by myocytes with asignificantly shorter action potential. The atrial neural network can bea major contributor in the progression from paroxysmal to persistent andlongstanding persistent AF by providing additional sources of rotors(reentry circuits) as well as focal drivers for initiation andmaintenance of AF. A gradient of atrial refractory periods (ARPs) ispresent from the PVG toward the atrial appendage and adjacent PV with aprogressive decrease of ARP and increase of AF inducibility with GPactivation. GP activation can also induce acetylcholine-mediated complexfractionated atrial electrograms (CFAEs) in the atrial myocardium, priorto the onset of AF, similar to the onset of AF at the PV-atrialjunction.

Thus atrial arrhythmias may be associated with disturbances in ECNS andICNS activity. Myocardial infarction (MI) induces morphological andneurochemical remodeling in the extrinsic stellate ganglion neurons,independent of infarct size, as reported by Ajijola et al, inpreclinical models. Changes cause neuronal enlargement of adrenergic andnon-adrenergic (cholinergic) neurons in both stellate ganglia as well asan increase in neuropeptide Y immunoactivity, neural cell adhesionmolecule (NCAM, a binding glycoprotein) and choline acetyltransferase(ChAT) inside the stellate ganglion (SG inset of FIG. 3B); Tyrosinehydroxylase (TH) decreases locally in the ganglion. Abnormal signalingfrom the left stellate ganglion and the left thoracic vagal nerve of theECNS causes AF and VF, as described in the following sections. However,bursts of activity in the ICNS, without input from ECNS or higherautonomic centers, can also trigger AF. Paroxysmal atrial tachycardiaand atrial fibrillation episodes were invariably preceded by intrinsiccardiac nerve activity. Local administration of drug formulations may beused to correct the abnormal nerve signaling from the ECNS and ICNS.Drug formulations may be applied at or near the cervical ganglia,stellate ganglion, PVGs, cardiac fat pads containing the GPs, gangliaand plexi in the atrial neuronal network and interconnecting nerves,axons, and glial cells. In one embodiment a drug formulation may beapplied at one or more locations to affect ECNS function. Drugformulations may be injected at or near the left stellate ganglion,right stellate ganglion, or both. In another embodiment, a drugformulation may be applied at one or more locations to affect ICNSfunction. In another embodiment, one or more drug formulations may beapplied to treat the ECNS and ICNS.

Structural remodeling of heart from injury can result in scar tissue.Scar tissue can cause the systemic excitation of the neuroendocrinesystem and increase the production of hormones/catecholamines likenorepinephrine (NE) and nerve-growth factor (NGF), as shown in FIG. 3B,near the sympathetic nerve terminal/junction between the cardiac nerveand cardiomyocyte (synaptic end of the extrinsic cardiac nerveoriginating at the stellate ganglion). The substances, along withcirculating plasma NE levels, result in neurochemical remodeling, nervesprouting (regrowth of nerves, reinnervation), or hyperinnervation inthe myocardium resulting in local anatomical and functionalneuromodulation at the cellular level. Cardiac hyperinnervation can alsobe caused by hypercholesterolemia, heart failure, and inflammation andis characterized by non-uniform increase in local nerve density. Thisprocess modifies the cardiac substrate and can lead to irregularities inthe propagation of electrical impulses through cardiac tissue.

Myocardial ischemia and nerve regrowth act to lower the threshold forcardiac arrhythmias, leading to atrial fibrillation (AF). Onceestablished, AF induces mechanisms for self-perpetuation CAF begetsAF′). The arrhythmias also induce structural, electrical, and autonomicremodeling superimposed upon pre-existing abnormalities to increasesusceptibility to recurrent and more persistent AF. For example, thereare several peripheral GPs located on the periphery of the atria. Theseperipheral plexi can also become independently hyperactive, particularlywhen separated from the major GP as a result of acute injury or chronicscarring.

Therefore, blocking the production of NGF, NE and other catecholaminesin cardiac nerve tissue through the local administration of drugformulations into the atrial myocardium can prevent nerve sprouting andpreserve the health of the cardiac substrate. As a result, the patientshave normal cardiac rhythm since the thresholds for AF inducibility aresustained and not lowered.

Radiofrequency (RF) ablation is currently used to treat atrialarrhythmias and has major limitations. Cardiac tissue ablation in theGPs has variable success rates; between 25-78% of patients were reportedto be free from AF at one year. Pulmonary vein ablation to isolate themfrom the cardiac nervous system (referred to as pulmonary veinisolation, or PVI), alone or in combination with GP ablation, is alsoperformed. PVI+GP ablation shows improved results. Atrial ablation ofmyocardial substrate, in regions that responsible for originating CFAEs,has also shown benefit to treat AF. But CFAE treatment effects are notdurable and repeat ablation procedures are needed. Moreover, theablation procedures are long. Some treatments require over 50 ablationsand can take 3-4 hours. They damage surrounding tissue and the treatmenteffects are not durable. Clinical procedures are described that may becompleted in less than 30 minutes. Drug formulations are targeted to acton neuronal circuits, conduction pathways, and tissue with reducedcollateral damage. They alter feedback loops inside the body that areresponsible for AF and provide durable treatment that lasts a few years.

Other treatment methods like low-level vagal nerve stimulation (LL-VNS),low-level carotid baroreceptor stimulation (LL-CBS) spinal cordstimulation (SCS) and renal denervation (RDN) are also in development totreat atrial arrhythmias. They involve the placement of multi-polarelectrodes, near at the T1-T4 level to stimulate the vagosympathetictrunk and the stellate ganglia T1 spinal level, connected to aneurostimulator which generates electrical pulses. Low level VNS, CBS,and SCS therapies are mediated by the parasympathetic branches of theECNS. They restore autonomic balance by increasing the central vagaltone through electrical stimulation and decreasing the sympathetic tonevia central reflex activation. While these therapies have demonstratedthe feasibility to suppress AF inducibility, the procedures requireinvasive surgery for the implantation of expensive generators andelectrical leads. Minimally-invasive and cost-effective methods aredescribed for treating atrial arrhythmias. Renal denervation therapy,alone or in combination with PVI, also shows promise to treat AF. Alltreatments need further clinical studies to show sustained clinicalbenefit.

In another embodiment, local chemo-neuromodulation (LCN) may be combinedwith one or more of the above procedures to treat atrial arrhythmias byacting on the extrinsic and intrinsic cardiac autonomic nerve pathwaysat two different nerve locations inside the body. Combinatorialtreatments may also be more effective in restoring autonomic balancebetween the sympathetic and parasympathetic feedback loops inside thebody. Examples include LCN+SCS and LCN+CBS and LCN+RDN.

Ventricular Arrhythmias, Electrical Storm, Cardiac Arrest and CardiacDeath:

Disruption of the ANS may lead to ventricular arrhythmias involvingincreased extrinsic central sympathetic drive or decreasedparasympathetic activity due to changes in density, distribution,excitability, and neurotransmitter content of the intrinsic efferentinnervation of the ventricles. Sympathetic hyperinnervation anddenervation are two prominent mechanisms responsible for ventriculararrhythmogenesis. Hyperinnervation occurs after injury to the myocardiumfrom MI, heart failure or inflammation as described above; NGFproduction leads to non-uniform nerve growth, as described by Fukuda etal. and illustrated in FIGS. 3A and 3B. Denervation is also caused byMI, diabetic neuropathy and HF from release of proNGF, the precursor toNGF, and chondroitin sulfate proteoglycans which trigger axonaldegeneration after myocardial infarction. Heterogeneities in cardiacinnervation and resultant effect on SNA is the one of the main reasonsfor arrhythmias.

At the macroscopic level, myocardial injury increases the synapticdensity of bilateral stellate ganglia of the ECNS. This increase in theganglionic activity suggests remodeling of the extrinsic cardiacautonomic nervous system that can lead to chronic stimulation ofsympathetic b-AR activity. Left stellate or right stellate ganglionstimulation is associated with ventricular tachyarrhythmias. Leftcardiac sympathetic denervation (LCSD) through surgical excision of thestellate ganglion, 2nd thoracic ganglion and 3rd thoracic ganglion hasbeen used to treat ventricular arrhythmias in high risk patientssusceptible to sudden death.

At the cellular level, sympathetic activation of the ECNS releases NE,which binds to beta-adrenergic receptor (b-AR), activates proteinkinase-A (PKA), phosphorylates several intracellular targets and leadsto shortening of the action-potential duration (APD). Locally high NEconcentrations also affect ion (calcium, sodium, potassium and protons)exchange and ion-channel function and cause focal arrhythmias.Shortening of APD during nerve conduction may increase the dispersion ofrepolarization (DOR) due to non-uniform innervation and resultingspatially non-uniform b-AR activation. These conditions are favorablefor early after depolarizations (EADs) and delayed after depolarizations(DADs). EADs may contribute to increased DOR, and both EADs and DADscontribute to ectopic activity and focal arrhythmias. While EAD isbelieved to contribute to atrial arrhythmias, DAD induces arrhythmias inventricular myocytes.

Hyperinnervation, nerve sprouting and localized release of NE (a b-ARagonist) affect the ICNS innervating the ventricle and increase the riskof ventricular arrhythmias. Chronic sympathetic denervation, on theother hand, can cause b-AR supersensitivity of myocytes, due to thedownregulation of G-protein receptor kinase 2 (GRK2, which inhibits b-ARduring stimulation). The loss of GRK2 combined with increase incirculating NE levels sets up a positive feedback loop that renders theventricular cardiac substrate arrhythmogenic. The local mismatch betweenthe adrenergic receptors in the heterogeneous (hyperinnervated anddenervated) myocardium prevents rhythmic signal conduction through theheart and causes arrhythmias. Cardiac nerves can also switch phenotype,i.e., transform from being adrenergic (NE-mediated signal conduction) tocholinergic (ACh-mediated nerve conduction) and render the cardiacsubstrate to be arrhythmogenic. Clinical studies with nuclear imaginghave shown that sympathetic denervation (hypoinnervation) is asignificant predictor ventricular arrhythmias, cardiac arrest and suddencardiac death.

These remodeling processes or loops, if uncorrected, can further damagethe ICNS in the cardiac substrate. The non-uniform sympatheticactivation increases the likelihood of focal arrhythmia triggers likeaction potential gradients, (or gradients in APD), EADs, DADs orincreased DOR, unidirectional conduction block, wave break, increasingthe susceptibility to reentrant arrhythmia (ventriculartachycardia/ventricular fibrillation, VT/VF). Differential spatial APDpatterns are observed in response to sympathetic stimulation (local NElevels) compared to circulating NE levels suggesting that the localheterogeneity in distribution of intrinsic ventricular nerve fibers is afactor in ventricular arrhythmias. During periods of high sympatheticactivity, like exercise or stress, these factors can invoke a perfectstorm of arrhythmic conditions that become uncontrolled due to thepositive feedback loops and cause cardiac arrest and sudden cardiacdeath. Data from the American heart association show that the incidenceof out-of-hospital cardiac arrest is nearly 7-fold higher in adults(between 50-79 years of age) with prior heart disease compared tohealthy patients. Among heart disease patients, the risk of cardiacarrest was two-fold and four-fold higher in prior-MI and HF patients,respectively.

A study of 1275 health maintenance organization enrollees 50 to 79 yearsof age who had cardiac arrest showed that the incidence ofout-of-hospital cardiac arrest was 6.0 per 1000 person-years in subjectswith any clinically recognized HD compared with 0.8 per 1000person-years in subjects without HD. In subgroups with HD, incidence was13.6 per 1000 person-years in subjects with prior MI and 21.9 per 1000person-years in subjects with HF.

Similar effects are noted on the ECNS induced stimulation of sympatheticactivity. Differential changes in regional myocardial polarization areobserved in animal models after stellate ganglion stimulation. RegionalDOR was greatest on the anterior wall of the left ventricle and the apexwith LSG stimulation. RSG stimulation causes the greatest dispersion onthe posterior wall and posterior base of the right ventricle. Local DORdid not correlate with shortening in action recovery intervalssuggesting that increased dispersion may be related to the sparse andheterogeneous innervation by stellate ganglia of the ECNS. Regionalchanges in DOR were consistent with T-wave changes observed duringinitiation of ventricular tachyarrhythmia.

Electrical storm (ES) is a more severe form of ventricular arrhythmia.It is a medical condition characterized by highly malignant and unstableepisodes of VT or VF, usually three or more episodes within a 24 hourperiod. ES mainly affects patients with advanced dilated cardiomyopathy,both ischemic and non-ischemic, with gradual progression of disease inthe arrhythmic substrate. It can also affect patients with structuralheart disease (aortic or mitral valve regurgitation, valvular leaks orcongenital heart disease), as well as patients without structural heartdisease (e.g., Brugada syndrome).

Currently ventricular arrhythmias (VT, VF, and ES) and ES are treatedusing drugs and implantable cardioverting defibrillators (ICDs) toprevent the initiation and propagation of the local arrhythmiasgenerated through neurohormonal, structural, and electrical remodelingprocesses occurring at the cellular level. Both ICDs and drugs are knownto prevent VT, VF, cardiac arrest and sudden cardiac death. Beta blockerdrugs reduce sympathetic activation, local NE production levels andarrest local arrhythmias. However, about 20-30% of patients are eithernot responsive or are intolerant to beta-blocker treatment. ICDs sensearrhythmias and, when they exceed a set threshold, send electrical shocksignals into the ventricles and arrest the propagation of the arrhythmicwave by preventing the positive feedback loop from becominguncontrolled. ICDs are very expensive and involve major surgery forimplanting an electrical generator and conduction leads. In addition,ICDs have also been reported to provide inappropriate shocks, which aretraumatic to patients, and affect their quality of life.

Treatments are described to overcome these limitations. In oneembodiment of, a method is described to treat ventricular arrhythmias byreducing the extrinsic cardiac nerve activity and b-AR activation bytreating the stellate ganglion, second thoracic ganglion and thirdthoracic ganglion through the administration of a drug formulation,locally at or near these ganglia and the interconnecting nerve chainfibers between them. The drug acts to block b-AR activity, attenuatestellate ganglion activity and reduce sympathetic stimulation of theheart through the ECNS. Formulations and methods to access and treat thestellate ganglion are described in the following sections.

In one embodiment, a drug formulation is injected locally at or near theleft-stellate ganglion to treat ventricular arrhythmias. In otherembodiments other ganglia of T2-T4 are also treated to reduce ANSactivity and treat VTs. In some cases, the preganglionic fibers mayextend to C7 and T5 ganglia. Methods and procedures are described toreach these ganglia and treat them by injecting small volumes of drugformulation. In other embodiments, the right stellate ganglion and itsadjacent chain ganglia from C7 to T5 and the interconnecting nervefibers may be treated.

Typically, nerve fibers from the left stellate ganglion widely innervatethe posterior wall of the ventricles, and those from the right stellateganglion are partially distributed in the anterior wall. However,cardiac disease (myocardial infarction and hypertrophy) can cause nervesprouting to extend to regions normally innervated by the left and rightstellate ganglia. In such cases, diagnostic sensing (nerve stimulationor cardiac imaging) may be used to confirm the nerve site location fortreatment and determine if the unilateral-left or unilateral-right orbilateral stellate ganglion treatments are needed. For example,stimulation of the stellate ganglia (right or left) or the ansaesubclaviae (right or left) may be performed to confirm target nervesthat innervate the scar tissue surrounding the infarcted myocardium.Alternatively, the myocardium may be imaged using iodine-123 MIBG toassess the local degrees of cardiac denervation and/or innervation todetermine if uni- or bi-lateral stellate ganglion treatment is needed.Stellate ganglion stimulation and MIBG imaging are described infollowing sections.

Another embodiment includes treating ventricular arrhythmias by localadministration of drug formulations, described below, into theventricular myocardium to reduce the heterogeneity of ICNS innervationand resultant sympathetic nerve signal transmission. The formulationsprevent cardiac denervation and/or hyperinnervation to maintainautonomic balance and reduce b-AR supersensitivity and increase thethresholds for the initiation and propagation of VT and VF. Suchformulations may be based on b-AR antagonists and other drugs asdescribed in detail in the following sections.

Thoracic epidural anesthesia by injection analgesics (like clonidine),LCSD and renal denervation have been used to treat patients that are athigh risk of death from VT/VF, cardiac arrest, electrical storm andsudden death. Analgesic effects are not long lasting and surgicalprocedures are invasive and expensive. These treatments are underinvestigation and used to treat high-risk patients that are refractoryto conventional treatments; clinical trials are needed to establishtheir long-term benefit. Minimally-invasive and cost effective methodsare described for treating ventricular arrhythmias which address theselimitations.

Another pathway to correct cardiac autonomic imbalance is by stimulatingthe parasympathetic ECNS. Direct stimulation of the cervicalpre-ganglionic parasympathetic fibers can enhance the cardiac vagal toneand prevent ventricular arrhythmias. Similarly, thoracic spinal cordstimulation (SCS) has demonstrated the potential to protect againstischemic ventricular arrhythmias in animal models. SCS also treatedspontaneous non-sustained VT and sustained VT in an ischemia reperfusionmodel. Both approaches are invasive, expensive and involve theimplantation of an electrical generator and leads. Minimally-invasiveand cost effective methods are described for treating ventriculararrhythmias and preventing cardiac arrest or cardiac death which addressthese limitations.

Another embodiment includes neuromodulating the afferent nerves, locatedat the T1-T4 thoracic dorsal root ganglia, through local administrationof drug formulations, described below. These nerve fibers transmitafferent nerve signals to the spinal cord. Interrupting the afferentsignaling reflex modulates the sympathetic efferent output to the heart.Porcine studies show that unilateral disruption of cardiac afferentinput to the spinal cord increased sympathetic tone to the heart, asnoted by a reduction in action recovery interval (ARI) and tachycardia,during stellate ganglion stimulation. Bilateral disruption showed nodifference in ARI or dispersion; a reduction in basal left-ventricular(LV) inotropic function and systolic blood pressure was noted.

Cardiac Channelopathies:

Channelopathy is a heart rhythm disorder that can potentially causefast, chaotic heartbeats. It is caused by disturbed function of ionchannel subunits of cells or the proteins that regulate ion channels.The disorders may be either congenital (due to mutations in the encodinggenes) or acquired (from autoimmune attack on the ion channel). Examplesof cardiac medical conditions affected by ion channel dysfunctioninclude long QT syndrome (LQTS), catecholaminergic polymorphicventricular tachycardia (CPVT), Brugada syndrome, and atrialarrhythmias. These conditions are most common in children and youngadults and, if left untreated, can cause syncope, cardiac arrest andeven sudden death. Current studies indicate that imbalance betweenparasympathetic and sympathetic nerve activity is one of the importanttriggers for the disease.

LQTS is a cardiac medical condition, characterized by abnormally longventricular repolarization, and increases the risk of irregular heartbeat that originates from the ventricles (ventricular tachyarrhythmias),also referred to as episodes of torsades de pointes (TdP). It is aneuronally-mediated disease that can lead to palpitations, syncope(fainting) and sudden death due to ventricular fibrillation, which canoccur during conditions of physical or emotional stress. Normally the QTinterval duration on an electrocardiogram (ECG/EKG) of a healthy personranges between 350-440 milliseconds. LQTS patients are considered to beat high risk for arrhythmias, when their QTc (defined as the ratio ofthe QT interval to the square root of the RR interval) is greater than500 milliseconds and low if QTc is less than 500 milliseconds.

LQTS may be genetic in origin resulting from gene mutation and differenttypes of LQTS (Types 1 through 13) depending on the mutation type havebeen identified. Type 1 (LQT1) and Type 2 (LQT2) are the most common,associated with mutations in potassium ion channels, and make up about50-65% of LQTS cases. Type 3 (LQT3) syndrome is associated with mutationin sodium ion channel. Sudden increases in sympathetic activity can leadto malignant VTs.

LQTS can also result from remodeling of the ICNS and ventricularsubstrate. EADs in LQTS patients are thought to be associated withreopening of L-type calcium channels during the plateau phase of thecardiac action potential. DADs are caused by an increased calcium-ionfilling of the sarcoplasmic reticulum. Adrenergic (NE-mediated)stimulation can increase the activity of these channels.After-depolarizations can propagate to neighboring cardiac cells due tothe differences in the refractory periods, leading to ventriculararrhythmias.

Malignant ventricular tachyarrythmias, associated with LQTS, can also beelicited by ECNS. Sudden increases in sympathetic activity, mostlymediated by the left stellate ganglion. Tissue samples of ganglia fromstellectomy-treated patients suggest that inflammation (or T-cellmediated cytotoxicity) of the sympathetic ganglion cells may boostadrenergic activity and trigger or enhance electric instability.

Beta blockers are the first treatment of choice and are shown to beeffective in preventing syncope in some patients. Additional treatmentsare necessary since 20-25% of patients continue to have syncopalepisodes and remain at high risk for sudden cardiac death despite theuse of beta blockers. ICDs are also implanted in LQTS patients, whenbeta blockers fail or are not well tolerated, to prevent VT and VF. ICDsalso have significant side effects, especially among young people, andare costly. Left cardiac sympathetic denervation (LCSD), by removingleft cervicothoracic or high thoracic left sympathetic ganglia(resection of the cervical sympathetic chain, also referred to asstellectomy), has been performed to treat patients suffering from LQTSand refractory to conventional treatment. Both stellectomy and ICDimplantations are surgically-invasive procedures.

Minimally-invasive methods are described to treat patients sufferingfrom LQTS by local neuromodulation of the left stellate ganglion througha one-time administration of a drug formulation, as detailed insubsequent sections. For some types of LQTS, both the left and rightstellate ganglia may be treated by local injection of drugs to resolvecardiac arrhythmic events. In other embodiments, one or more or aportion of the cervical and thoracic ganglia may be treated usingmethods and formulations described below.

CPVT is another lethal cardiac ion channelopathy causing arrhythmiasfrom ion-channel dysfunction and inappropriate handling of calciumrelease in cardiomyocytes due to unbalanced autonomic innervation of theheart. Like LQTS, it affects children and young adults. The arrhythmiascause syncope, seizure, cardiac arrest and sudden unexpected death(SUD). Nearly 30% of patients experience SUD as an initial presentationand up to 50% experience cardiac arrest by the age of 20-30. Althoughbeta blockers are the standard therapy for CPVT, they are not welltolerated in some patients and treatment failure is reported in others.Limited studies have shown that CPVT patients can benefit from LCSD andplacement of ICDs. Limitations on ICDs include cost and inappropriateshocks and the incidence of electrical storm in about 20% of patients.Both ICDs and LCSD are surgically invasive procedures.Minimally-invasive and cost-effective methods are described to treatCPVT.

Myocardial Infarction:

Patients who survive acute myocardial infarction (AMI) have a highincidence of ventricular arrhythmia and risk of sudden cardiac death(SCD). MI induces neural and electrical remodeling at scar border zones,as previously described, causing nerve sprouting (see FIGS. 3A and 3B).Acute arrhythmias may be caused by re-entry circuits in the damagedmyocardium from coronary artery occlusion or reperfusion immediatelyafter revascularization. Late ventricular tachycardias may result fromre-entrant circuits in the healed-infarct and peri-infarct zones.Increased cardiac sympathetic activation worsens dispersion ofrepolarization (DOR) in the myocardium and renders it proarrhythmic.Studies have also shown that APDs and electrophysiological (EP)characteristics vary between myocytes in the three myocardial layers ofthe heart. The mid-myocardial myocytes have longer APDs than theepicardial and endocardial myocytes. Following myocardial injury, the EPcharacteristics of the ventricular substrate are altered by ICNSremodeling, which leads to the amplification of the DOR, causingventricular transmural reentrant arrhythmias. In addition, variousadrenergic receptors can mediate the cardiac ventricular EP effects fromefferent sympathetic nerve activity relative to effects from circulatingsystemic NE levels.

Excessive ECNS sympathetic activity of the left stellate ganglion (LSG)nerve activity is also attributed to the initiation of ventriculararrhythmias. Stimulation or the infusion of nerve growth factor to theleft stellate ganglion in dogs, that suffered MI, intensified themagnitude of LSG activity and caused a high incidence of SCD. Targetedattenuation of cardiac sympathetic neurons in the stellate gangliareduced the incidence of MI-induced sustained VT in rats. Blocking theLSG activity in rabbits prolonged APD (in all three layers), reducedtransmural DOR and increased the effective refractory period (ERP) andthe ventricular fibrillation threshold (VTF). Thus reducing ECNSsympathetic activity may also benefit MI patients.

Currently patients suffering from myocardial infarction are treatedusing drugs, an interventional procedure or coronary artery bypass graft(CABG) surgery. Drugs are used to dilate arteries and increase bloodsupply and oxygen to the myocardium. A percutaneous coronaryinterventional (PCI) procedure, involving a balloon, stent, or adrug-eluting stent, is performed to open occluded arteries and restoreblood flow. When the vessel blockages are complex, open CABG, off-pumpCABG, or beating-heart surgical methods are used to treat patients andincrease the supply of oxygen to the myocardium. However, a significantnumber of patients suffer episodes of atrial and ventricularfibrillation after these treatments.

Nearly 1 in 2 patients experiencing an acute MI (AMI), usually in theform of ST segment elevation MI (STEMI), are at risk of sudden cardiacdeath before receiving medical attention. Survival rates improved in thepast two decades due to the increasing use drugs (beta-blockers,statins, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin-IIreceptor blockers (ARBs), and anti-platelet drugs), rise in PCIprocedures (reperfusion therapy to open blocked coronary arteries), andreduction in door to balloon time (improved medical attention). However,post-MI patients still have a life-long risk of ventricular arrhythmiasand SCD that is nearly four times higher compared to the generalpopulation. Current in-hospital mortality rates after acute MI rangebetween 5-6%; 1-year mortality rates range between 7-18%. Diabetic,dialysis, and kidney disease patients perform far worse, and nearly 70%of coronary artery disease (CAD)-related deaths in these populationspresent as cardiac arrest prior to presenting to hospital. A large studyon patients treated by PCI after MI reported that 30-day, 1-year, and5-year cardiac mortality rate were 7.3%, 8.4%, and 13.8%. The maincauses of early death within 30 days are cardiogenic shock, brain damage(due to cardiac arrest) and malignant arrhythmia.

Malignant arrhythmias are reported in AMI and MI patients after PCIintervention. Secondary prevention of SCD can be achieved through ICDimplantation, when malignant ventricular arrhythmias occur late (>48 h)after an MI, and are not due to reversible or correctable causes.Clinical guidelines for the primary use of ICDs to prevent SCD duringthe first 1-3 months after ST-elevation MI for patients who have lowLVEF are evolving. ICDs may implanted in patients developing syncope ornon-sustained VT, who have inducible sustained VT at the EP study, andin patients with an indication for a permanent pacemaker due tobradyarrhythmias. As noted, previously ICDS are invasive and expensive.Similarly, 20-40% of patients after cardiac surgery (coronary arterybypass grafting and cardiac valve replacement) suffer from abnormalheart rhythm 2-4 days after the procedure. This lengthens the hospitalstay and Increases their risk of perioperative stroke and mortality. AFis the most common form of arrhythmia with onset occurring within 48hours after surgery. The episodes may spontaneously convert to sinusrhythm or may persist over a week and require treatment to restorenormal rhythm. HF and SCD accounted for nearly two-thirds of cardiacdeaths in patients after trans-aortic valve replacement (TAVR). LVEF andnew-onset persistent left bundle-branch block following TAVR wereindependent predictors of SCD.

Minimally-invasive methods are described to treat patients sufferingfrom acute MI (with or without ST-segment elevation), angina, MI andcardiac valvular disease local neuromodulation of the left stellateganglion through a one-time administration of a drug formulation, asdetailed in subsequent sections. Not only does this treatment preventthe occurrence of VT/VF episodes, but it also resets the autonomicbalance and decelerates the deterioration in the cardiac substrate andprogression of disease. Attenuation of stellate ganglion activity mayalso be supplemented by the injection of a different drug formulationinto regions of the ventricular myocardium to treat the maladaptivechanges in the ICNS. In other embodiments, one or more or a portion ofthe cervical and thoracic ganglia may be treated using methods andformulations described below.

Treatments described may be used as an adjunctive treatment to othertreatments like PCI and CABG. Stellate and thoracic ganglia may bepreemptively treated by local chemical neuromodulation before coronaryballoon angioplasty, stenting or bypass surgery to reducepost-interventional or post-surgical complications. Local drugadministration may be done a few weeks to a few months, such as between3 weeks to 3 months, prior to currently-accepted treatments for MI orvalve repair to allow sufficient time for reduction in catecholaminelevels.

Cardiomyopathy:

Cardiomyopathy (CM) is a medical condition associated with deteriorationin the heart muscle, and its ability to contract and pump blood, leadingto heart failure. It can take many structural forms—dilated,hypertrophic and restrictive, all of which impair heart pump function.Patients with CM are at risk for irregular heart rate and sudden cardiacdeath.

The use of ICDs to prevent sudden cardiac death has resulted in anincreasing number of patients presenting with recurrent, appropriate ICDshocks for VT. Since pharmacologic therapy has not shown benefit, VTablation is commonly used to treat patients with limited long-termefficacy and significant complications. The ThermoCool VT ablation trialreported recurrence of VT in 47% of patients at 6 months and aperi-procedural complication rate of 7.3%. Therefore, adjunctive oralternative treatment approaches are desirable in this patientpopulation

Since the modulation of the ANS can be used to treat ventriculararrhythmias, methods are described to treat cardiomyopathy patients bylocal neuromodulation of the left stellate ganglion through a one-timeadministration of a drug formulation, as detailed in subsequentsections. In some cases, both the left and right stellate ganglia may betreated by local injection of drugs to resolve cardiac arrhythmicevents. In some cases, treatment may be administered at or near thestellate ganglion and in the myopathic cardiac substrate. In otherembodiments, one or more or a portion of the cervical and thoracicganglia may be treated using methods and formulations described below.

Heart Failure:

Heart failure is another ANS-mediated cardiac disease, influenced bycomplex neurohormonal mechanisms, which impairs the ability of the heartto pump blood. Most prominent among the neurohormonal mechanisms is theelevated adrenergic or SNS activity. In healthy hearts, the activationof ANS following cardiac injury restores cardiac function and output.For example, the SNS (adrenergic) branch of the ANS accelerates heartrate (positive chronotropy, predisposing to arrhythmias), increasescardiac contractility (positive inotropy) and cardiac relaxation(positive lusitropy), a decrease in venous capacitance, and constrictionof blood vessels, all of which increase cardiac output as part of thebody's fight-or-flight response. The parasympathetic (cholinergic)branch slows the heart rate (bradycardia) through vagal nerve impulseswith minimal effect on cardiac contractility. Cardiac ventricles, thatpump blood into the systemic and pulmonary circulations, are primarilyinnervated by adrenergic sympathetic nerves. Cholinergic parasympatheticfibers run alongside the vagus nerve sub-endocardially with minimal PSNSinnervation to the ventricular myocardium. Thus, while heart rate can becontrolled by SNS and PSNS, cardiac output is mostly controlled by theSNS. When the injury persists over time, the ANS is unable to maintaincardiac function; the hyperactive ANS activates the heart to work harderthan the cardiac muscle can handle, resulting in a failing heart. ANShyperactivity becomes a major problem in HF, conferring significanttoxicity to the failing heart, and markedly increasing the morbidity andmortality of patients.

The cardiac neuronal system comprises afferent, efferent, andinterconnecting neurons which behave as a control system. Afferentfibers project to the CNS by the autonomic nerves, whereas efferentimpulses travel from the CNS to peripheral organs. The ANS outflow tothe heart and peripheral circulation is regulated by cardiovascularreflexes originating from the aortic arch and the carotid baroreceptorsand cardiopulmonary baroreceptors that are responsible for ANSinhibition, and cardiovascular low-threshold polymodal receptors andperipheral chemoreceptors, which are responsible for ANS activation.

ANS activation in the cardiovascular system is mediated bynorepinephrine and epinephrine through the following steps: (a) NE isreleased by cardiac sympathetic nerve terminals located in the rightstellate ganglion reaching the sinus and atrioventricular nodes(increase in heart rate and shortening of atrioventricular conduction)and through the left stellate ganglion reaching the left ventricle(increase in contractile strength), although NE release and reuptake canoccur systemically throughout the heart and body; (b) epinephrine isreleased systemically into the circulation by the adrenal medulla,affecting both the myocardium and peripheral vessels; and (c) localrelease of NE and epinephrine by various peripheral ANS's that cansynthesize and release these catecholamines in an autocrine/paracrinemanner and are located in blood vessels and in cardiomyocytes.

Systolic HF is associated with neurohormonal hyperactivity as acompensatory mechanism to maintain cardiac output as cardiac functiondeclines. Neuronal part is caused by ANS cardiac nerve terminals and thehormonal part is caused by increased secretion of NE, epinephrine,angiotensin II, and aldosterone hormones. ANS hyperactivity is noted asincreased plasma NE and epinephrine levels, elevated (central)sympathetic outflow, and elevated NE spillover from activated cardiacsympathetic nerve terminals into the circulation. Systolic HF patientsmay, in fact, have a decreased ANS neuronal density and function,resulting in decreased NE concentration in the heart. Depletion ofcardiac ANS neuronal NE stores (from reduced beta-adrenergic receptordensity) and impaired neuronal NE reuptake via the NE transporter (fromchronic overstimulation of adrenergic receptors) can cause a netenhancement of NE release and lead to worsening of HF failure, changesin receptor signaling, cardiac remodeling and sudden death.

Cholinergic remodeling can also occur in HF patients fromneurotransmitter plasticity in the sympathetic ganglia in conjunctionwith postsynaptic receptors on cardiomyocytes, as noted by Fernandez andCanty. In the normal hearts, extrinsic cardiac nerves originating fromthe stellate ganglion secrete NE, increase heart rate and myocardialcontractility through b1-adrenergic receptor signaling. The synaptic orinterstitial NE level is the net amount of NE released and amount ofreuptake. In HF patients, neuronal plasticity causes some cell bodies inthe sympathetic ganglia to transdifferentiate into cholinergic type,expressing choline acetyltransferase (ChAT) causing a decrease in THexpression (see SG inset in FIG. 3B). The change from adrenergic tocholinergic type is promoted by NGF released from the myocardium,leukemia inhibitory factor (LIF) and cardiotrophin-1 expression. LowerNE reuptake and higher circulating NE levels (from sympathetic nerveoveractivity) elevate interstitial NE and cause a reduction in theb1-receptor density and b-adrenergic signaling. In HF, cardiomyocytesalso increase the expression of muscarinic (M2) receptors which canfurther reduce b-adrenergic activity and cause bradycardia and reducedcontractility leading to diminished pumping inefficiency of the heart.

The role of chronic ANS activation in diastolic HF, without impairedleft-ventricular ejection fraction (LVEF), is limited. ANS hyperactivitymay contribute LVEF dysfunction in hypertensive patients and increasetheir risk to develop HF.

Patient symptoms of HF are classified according to the severity of theirsymptoms into four categories based on the New York Heart Association(NYHA) Functional Classification. Class I patients have no limitation ofphysical activity. Class II patients have mild limitation on physicalactivity. Ordinary physical activity results in fatigue, palpitation, ordyspnea (shortness of breath). Class III patients have marked limitationof physical activity and less than ordinary activities cause fatigue,palpitation, or dyspnea. Class IV patients are unable to carry on anyphysical activity without discomfort.

Medical management of chronic HF has shown benefit in some patients andis currently the best treatment of heart failure. Heart failure patientsmay need multiple medications including ACE inhibitors, ARBs, betablockers and angiotensin-receptor neprilysin Inhibitors (ARNIs),hydralazine and isosorbide dinitrate, aldosterone antagonists, anddiuretics.

Device-based therapies are used to supplement care in patients withadvanced HF. Cardiac resynchronization therapy (CRT) is the mostsuccessful device-based therapy which improves the synchronizationbetween the left ventricle and right ventricular apex through electricalstimulation (pacing) using an implantable generator and a lead, similarto an ICD. CRT is recommended in patients with a left bundle branchblock (LBBB) pattern, LVEF<=35%, QRS duration >150 milliseconds, andclass III or IV symptoms. A major limitation of CRT is that it cannottreat all HF population. It treats a quarter of HF patients thatprolonged QRS duration; as many as 18-52% of patients receiving CRT arenon-responders. Cardiac contractility modulation (to improve ventricularcontractile function independent of QRS, by delivering a non-excitatoryelectrical signal during the refractory period of the cardiac cycle),vagus nerve stimulation (of preganglionic parasympathetic neurons in thebrain stem), spinal cord stimulation (of the spinal nerve fibers leadingto increased vagal tone and decreased sympathetic tone), carotid sinusstimulation (of the baroreceptors that activate efferent vagal nervefibers), controlled interatrial shunts, and ventricular restorationdevices are also in development. In extremely severe cases aleft-ventricular assist device (LVAD) is also implanted as a bridge to aheart transplant or for long-term therapy. Heart transplant is the lastoption for patients that do not benefit from drugs and devices. As canbe appreciated, all these treatments require invasive surgery, for theplacement of an implant or electrical generator with leads, and areexpensive.

Treatments are described which treat HF by affecting (the neurohormonaland electrical pathways of) the ANS through local neuromodulation of thestellate ganglion using drug formulations detailed in subsequentsections. One or both (left and right) stellate ganglia may be treatedby local injection of drugs to affect the cardiac ANS, correct thecardiac conduction pathways, and improve left ventricular function ofthe heart to prevent cardiac arrest and sudden cardiac death. In somecases, drugs may be administered at two locations, the stellate ganglionand in the diseases cardiac muscle. In other embodiments, one or more ora portion of the cervical and thoracic ganglia may be treated usingmethods and formulations described below.

Chagas Disease:

Chagas disease is a tropical parasitic disease that is spread mostly byinsects. It affects 7-8 million people in Mexico, South America, andCentral America, and led to 12,500 deaths in 2006. The disease occurs intwo stages, an acute stage and a chronic stage. The chronic stagedisease symptoms develop 10-30 years after the initial infection (acutestage) in between 30-40% of patients. Among those, 20-30% of patientsthe chronic damage affects the ANS, digestive system, and the heart.Cardiac damage causes enlargement of the ventricles (dilatedcardiomyopathy), heart rhythm disturbances, and heart failure. Patientsare treated by drugs (amiodarone, beta blockers, ACE inhibitors,lidocaine and propafenone), ICDs, or cardiac tissue ablation.

Treating the ANS through renal denervation has been shown to reduceVT/VF episodes in patients suffering from Chagas disease despite theimplantation of an ICD, refractory to medical therapy and cardiacablation. Methods are described to treat cardiac and other ANS-mediateddisorders caused by Chagas disease through neuromodulation of the ANS bylocal injection of drug formulations at or near the stellate ganglion,as described in the subsequent sections. One or both (left and right)stellate ganglia may be treated by local injection of drugs to affectthe cardiac ANS, correct the cardiac conduction pathways, and improveleft ventricular arrhythmias to prevent HF, cardiac arrest, and suddencardiac death.

Other Cardiac Conditions:

Other ANS-mediated cardiac and cardiovascular disease conditions includeangina, post-MI rehabilitation, microvascular ischemia, acute coronarysyndrome, shock (hypovolemic, septic, neurogenic), valvular disease,cardiac structural abnormalities such as septal defects, myocardialcontractility disorder, hypertension, orthopnea, dyspnea, orthostatichypotension, dysautonomia, syncope, vasovagal reflex, carotid sinushypersensitivity, and pericardial effusion.

Modulation of the autonomic nervous system (ANS) is emerging as aneffective therapy to prevent such pathophysiological progress in cardiacdisease. Various nerve targets have been identified as potential sitesto modulate autonomic function. Examples include high-thoracic epiduralanesthesia (HTEA), low-level vagal nerve stimulation, baroreflexstimulation, and renal nerve stimulation, ablation of GP in the heart,carotid body ablation, and stellate ganglion ablation. HTEA reducesafferent and efferent sympathetic nerve impulses to the heart and isused to stabilize cardiac electrical function. Bioelectric therapies,applied to the thoracic dorsal column or cervical to paravertebralsympathetic chain, can modulate ANS and reduce arrhythmias.

Methods are described to treat cardiac disease by locallyneuromodulating the ANS, at nerve sites along the sympathetic chain ofganglia, that run along both (left and right) sides of the spinal cordand interconnecting nerve fibers nerves between them. Nerves, ganglia,plexi, ganglionated plexi, sympathetic nerves, and portions of ganglia,plexi, nerves, and nerve fibers inside the body are accessed usingvarious devices, visualized and treated using drug formulations.Neuronal activity is monitored before, during, and after treatment toensure completeness of treatment. Drug formulations are described thatact on neuronal tissue and affect local ANS activity to treat cardiacdisease without detrimental effects associated with systemic daily useof drugs, their side effects, and potential organ damage. Treatments aredesigned for a one-time administration of a small volume of the drugformulation at or near the nerve target sites to treat disease, and theefficacy is expected to last 1 day to over ten years, depending on theclinical application.

In one embodiment, a method of modulating the nerve activity at thecervicothoracic sympathetic ganglion (also referred to as the stellateganglion) and nearby sympathetic nerves, nerve fibers, and neurons isdescribed by locally delivering a drug formulation. Stellate ganglionablation treatment was introduced in 1971 for adrenergically-mediatedlife-threatening ventricular arrhythmias to prevent sudden cardiacdeath. The procedure increases the threshold for causing arrhythmias bycompletely resecting the entire left stellate ganglion through surgery.In humans, the stellate ganglion is star-shaped structure, measuringabout 1.5 cm3, situated lateral and posterior to the lateral edge of thelongus colli muscle anterior to the first rib and posterior to thesubclavian artery. It results from the fusion of the inferior cervicalganglion and the first thoracic ganglion into a single nerve body. Whilemost individuals have a fused anatomy, unfused ganglia that lay in asimilar area anterior to the transverse process of the C7 vertebra arealso observed. Preclinical studies in dogs have shown that removing thestellate ganglion can increase VF thresholds, decrease cardiacexcitability, and reduce the incidence of arrhythmias after myocardialinfarction. In particular, the left stellate ganglion (LSG) is often thetherapeutic target since left-sided cardiac sympathetic nerves havehigher arrhythmogenic potential, increased dispersion of refractoriness,promote reentry and enhance automaticity. For example, NGF injectioninto the LSG caused sympathetic nerve sprouting, prolonged QTc intervaland increased the risk of SCD (50%) in an experimental dog model.Similar NGF treatment on the right stellate ganglion shortened QTc anddid not cause SCD, despite nerve sprouting.

Another method to regulate autonomic function by modulating cardiacnerves is left cardiac sympathetic denervation (LCSD), also referred toas high thoracic left sympathectomy (HTLS). LCSD involves surgicalablation or removal of the lower ½-⅔rd of the left stellate ganglion andthe T2, T3, and T4 (and sometimes the T5) thoracic ganglia. Thisprocedure provides adequate denervation and is associated with minimaleffects of Homers syndrome.

Methods are described to treat the left stellate ganglion and nearbythoracic ganglia, sympathetic nerves, rami communicantes, nerve fibers,and portions of nerve or nerve fiber through the local administration ofa small volume (for example, approximately 0.01-20 mL) of drug tomodulate or ablate the lower half of the left stellate ganglion and T2,T3, and T4 thoracic ganglia. The drug may be administered using a needleunder fluoroscopic (X-ray), CT, or ultrasound guidance to using thecervical and thoracic vertebral landmarks. Drug formulations, methods ofadministration, and visualization methods are described in detail insubsequent sections.

Drugs may be delivered locally into other anatomical locations of theheart to treat cardiac disease. The heart is innervated by endocardial,myocardial, epicardial, and pericardial nerve fibers. A small volume ofa drug may be injected into selective regions within these layers. Thepericardium is a protective sac which contains a small amount of fluid.Drug formulations described in the sections below may be injected intothe pericardial sac to affect nerves or ganglia innervating the heartand restore autonomic balance.

Other anatomical targets inside the body may also be treated to regulatethe autonomic nervous system and treat cardiac disease. For example,denervation of renal nerves near the kidney has been shown to decreasesympathetic nerve activity and plasma norepinephrine levels and treatatrial fibrillation. The carotid body is another target for modulatingsympathetic nerve activity to treat heart failure.

Non-Cardiac Medical Conditions and Therapies

Pulmonary Hypertension:

Recent studies have shown that the SNS is activated in pulmonaryarterial hypertension (PAH) patients, in addition to the known imbalanceof vasoactive mediators like nitric oxide and arginase. Abnormalsympathetic hyperactivity has been shown to be an independent indicatorin patients with PAH to show decreased functional capacity compared tothose with normal sympathetic tone.

Most PAH patients are currently managed on oral drugs that are takendaily. Newer treatments are currently in development. Pulmonary arterydenervation in the main pulmonary artery has been shown to treat PAH inexperimental studies. Sympathetic ganglion block, by injecting a localanesthetic to the superior cervical ganglion, in rats(monocrotaline-induced PAH model) showed a reduction in the medial wallthickness of muscular pulmonary arteries compared to controls andattenuate the progression of PAH disease.

Methods are described to treat PAH through neuromodulation of the SNSand ganglia of the sympathetic chain. A small volume (for example,approximately 0.01-20 mL) of a drug may be administered at or near theleft superior cervical ganglion to one or more of modulate, block, andablate the nerves and reduce sympathetic nerve overactivity.Formulations are described in the following sections to achieve thedesired extent of nerve modulation and the treatment time period. Thedrug may be administered using a needle under fluoroscopic (X-ray), CT,or ultrasound guidance to using the cervical and thoracic vertebrallandmarks. Drug formulations, methods of administration, andvisualization methods are described in subsequent sections.

Hot Flashes, Chronic Regional Pain Syndrome and Post-Traumatic StressSyndrome:

Hormone replacement therapy (HRT) is currently in clinical practice forthe treatment for hot flashes in symptomatic women with a clinicalefficacy of 80%-90%. However, HRT is not recommended for patients withbreast cancer. There are reports indicating that stellate ganglion block(SGB) for the treatment of vasomotor symptoms in symptomatic women, witha diagnosis of breast cancer are promising, may be effective.

Chronic or complex regional pain syndrome (CRPS), also known as reflexsympathetic dystrophy (RSD), is a medical condition that ischaracterized by pain, swelling, and vasomotor dysfunction of anextremity (limb, neck, chest, or head-termed CRPS Types I and II). It isoften therapy-resistant with an unclear pathophysiology andunpredictable clinical course. Women are more affected than men.Sympathetic block is the currently used to treat CRPS. Nerve block ofthe stellate ganglion is achieved by repeated injections of a localanesthetic agent (lidocaine, bupivacaine, morphine), guanethidine, or byradiofrequency ablation, or by phenol neurolysis. Lumbar and cervicalsympathetic blocks and plexus brachialis block are also performed usinglocal anesthetic injections. Spinal cord and peripheral nervestimulation (with surgically placed electrodes and generators) are alsounder evaluation. Sympathetic block treatments for CRPS, however, maynot be durable; they also require multiple daily injections over severalweeks. Implant-based therapies like spinal cord or peripheral nervestimulation are invasive and expensive. Irradiation using linearpolarized near-infrared light therapy has been used to treat CRPS withmixed results. Two out of six patients reported a reduction in pain, andfour patients noted minimal or no improvement; no significant changes inautonomic function were noted. Besides, irradiation therapies aredifficult to localize the treatment to the stellate ganglion and maydamage surrounding tissue.

Post-traumatic stress disorder (PTSD) is a chronic anxiety disordercaused by seeing or experiencing traumatic events. Symptoms includeanxiety, anger, or hypervigilance with clinically significant distressand/or functional impairment over an extended period of time. The SNS isknown to be chronically activated (with higher NE levels incerebrospinal fluid and urine) over the normal baseline levels in PTSDpatients. Such high SNS activity among PTSD patients suggests thatreducing noradrenergic activity in the central nervous system (CNS)could provide therapeutic benefit. Prazosin (a sympatholytic,alpha-adrenergic blocker) and clonidine (alpha-2 adrenergic receptorantagonist) are two drugs used to treat PTSD. Cervical sympatheticsystem modulation is also used to treat PTSD. The stellate ganglion andupper thoracic ganglion (T-2) are the upper sympathetic ganglions thatinnervate the upper chest, the head, and the brain. Many of the efferentsympathetic fibers from the thoracic ganglia (T-2) pass through thestellate ganglion. Clipping the sympathetic ganglia, via an endoscopicsympathetic block, at the T2 thoracic vertebra was found to besuccessful in treating PTSD. Studies on SGB, using a long-actinganesthetic in a group of nerves in the cervicothoracic ganglion, arealso underway to treat PTSD.

Shingles (or herpes zoster) is a medical condition that is characterizedby a painful and debilitating skin rash caused by the varicella zostervirus. It usually appears in a band, strip, or a small region of theface of the body. The virus causes chicken pox and following treatmentstays dormant in the nerve roots. In some patients, the virus becomesactive again through stress, age, and disease and weakens the immunesystem. Stellate ganglion block (SGB) and intercostal nerve blocktreatments are currently performed by pain specialists to treat painfrom shingles.

Hyperhidrosis is a medical condition associated with excessive andunpredictable sweating even when the patient is at rest or thetemperature is cool. The condition may be treated by antiperspirants andmedications. More complex treatments involve underarm surgery to removethe sweat glands in the armpits by cutting, lasers, scraping, orliposuction. Iontophoresis therapy, using a gentle current ofelectricity, is also to treat sweating of the hands and feet. Injectionof botulinum toxin into the underarm to block the nerves that stimulatesweating is also a treatment option; side effects include injection sitepain and flu-like symptoms.

Endoscopic thoracic chain sympathectomy and stellate ganglion block areperformed to treat severe forms of facial, palmar, and plantarhyperhidrosis. The second thoracic sympathetic ganglion is consideredthe major innervation center connected to the upper extremities, andhence, is the main target nerve site for nerve block or sympathectomy totreat hyperhidrosis. Surgical sympathectomy to treat palmarhyperhidrosis involves the removal or electrical cauterization orablation of the T2 and/or T3 sympathetic ganglion. Compensatoryhyperhidrosis (CH) is the most common complication of sympathectomy.Another technique involves a simple disconnection (excision) of thesympathetic chain between the T2 ganglion and the stellate ganglion,thereby preserving the ganglia. This procedure, known as sympathotomy orsympathicotomy, produces excellent results and clinically diminishes thechances of severe CH. Ramicotomy is another surgical procedure whichdisconnects or removes a section of the sympathetic (gray) rami, whichconnect the stellate ganglion to the brachial plexus, and treatshyperhidrosis, as shown in FIG. 1D. Both ramicotomy and sympathicotomyare under evaluation for the postoperative risk of severe CH.

Other complications of stellate ganglion block using a percutaneousneedle-based approach or a video assisted thoracic approach includedamage to the brachial plexus, trauma to the trachea and esophagus,injury to the pleura and the lung (pneumothorax or hemothorax), bleedingat the injection site, and hematoma. Airway compression and vasovagalcan also occur along with infectious complications, when there is abreach in the aseptic barrier, including local abscess, cellulitis, andosteitis of the vertebral body and transverse process. Hoarseness of thevoice due to paralysis of the recurrent laryngeal nerve and respiratorydistress due to paralysis of the phrenic nerve are pharmacologicalcomplications associated with variabilities in the volume, dose, type,and exact injection site of the anesthetic formulation. Other adverseevents may include seizures, loss of consciousness, hypotension, airembolism, and bradycardia.

Although the exact mechanism for hot flashes, CRPS, and PTSD are notexactly clear, it has been postulated that they could have commonorigins. In women, estrogen is known to regulate the production of nervegrowth factor in sympathetic nerves. A decrease in estrogen leads to anerve growth factor increase, which increases norepinephrine (NE) levelsin the brain mediated by an overactive SNS. Stellate-ganglion block(SGB), results in a reduction in SNS activity and NE levels. Thisinteraction leads to a reduction of many symptoms associated with theseconditions. For example, nerve growth factor increases in pathologicalstates with chronic stress. Hypoxia, neurogenic inflammation (byexcretion of neuropeptides from nociceptive C-fibers) and sympatheticdysfunction are cited as potential causes for CRPS. Higher adrenergicSNS activity and circulating NE levels have been reported in PTSDpatients compared healthy patients.

Methods are described to treat hot flashes through neuromodulation ofthe SNS and ganglia of the sympathetic chain. A small volume (forexample, approximately 0.01-20 mL) of a drug may be administered at ornear the left stellate ganglion to one or more of modulate, block, andablate the nerves and reduce sympathetic nerve overactivity.

Methods are described to treat CRPS I and II conditions throughneuromodulation of the SNS and ganglia of the sympathetic chain. A smallvolume (for example, approximately 0.01-20 mL) of a drug may beadministered at or near one or more of the stellate ganglion, thoracicganglia, lumbar ganglia, and the brachial plexus n to one or more ofmodulate, block, and ablate the nerves and reduce sympathetic nerveoveractivity.

Methods are described to treat PTSD through neuromodulation of the SNSand ganglia of the sympathetic chain. A small volume (for example,approximately 0.01-20 mL) of a drug may be administered at or near oneor more of the cervical ganglia, stellate ganglion, and thoracic gangliato one or more of modulate, block, and ablate the nerves and reducesympathetic nerve overactivity.

Methods are described to treat shingles through neuromodulation of theSNS and ganglia of the sympathetic chain. A small volume (for example,approximately 0.01-20 mL) of a drug may be administered at or near thestellate ganglion and/or the intercostal nerve to one or more ofmodulate, block, and ablate the nerves and reduce sympathetic nerveoveractivity.

Methods are described to treat hyperhidrosis through neuromodulation ofthe SNS and ganglia of the sympathetic chain. A small volume (forexample, approximately 0.01-20 mL) of a drug may be administered at ornear the second (T2) and/or third (T3) thoracic ganglia to one or moreof modulate, block, and ablate the nerves and reduce excessive sweating.Depending on the location and severity of hyperhidrosis, other targetnerve locations for neuromodulation and nerve block include thesympathetic chain connections between the ganglia (e.g., the chainbetween T2 and T3 ganglia), the stellate ganglion, portions of thestellate ganglion, other thoracic ganglia, and chains between gangliafor the treatment of hyperhidrosis.

The drug may be administered using a needle under fluoroscopic (X-ray),CT, or ultrasound guidance to using the cervical and thoracic vertebrallandmarks. Formulations are described to achieve the desired degree ofnerve modulation over the treatment time period. For example, the nervesmay be blocked temporarily for a few hours or a few weeks. Nervefunction may be excited (upregulated) or impaired (downregulated) usingdrug compositions and concentrations. Nerves and nerve function may alsobe permanently impaired preventing nerve regrowth and regeneration. Drugformulations, methods of administration, and visualization methods toachieve the above are described in detail in subsequent sections.

Stroke and Vasospasm:

Stroke is a major cerebrovascular disease that is caused by a blockedblood vessel or bleeding (hemorrhage) in the brain. Specifically,cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) cancause a 1.5- to 3-fold increase in mortality within the first 2 weeksafter SAH. When patients survive stroke, it is the major cause of majordisability, with a 25% reduction in excellent outcome. Currenttreatments for cerebral vasospasm consist of hypervolemic, hypertensive,hemodilutional (HHH) therapy, and neuroradiological procedures. Thesetreatment options have technical limitations and have demonstratedsignificant variability in clinical outcomes.

New approaches targeting the ANS, with temporary block of theintracranial autonomic sympathetic inflow, have shown to improvecerebral blood flow in humans and preclinical models. Perivascularsympathetic nerves play an active role on the regulation ofcerebrovascular resistance. The cerebral vasculature in the pial vesselsis densely supplied by noradrenergic sympathetic nerve fibersoriginating in the superior cervical ganglion, running along the carotidartery, and projecting into the ipsilateral hemisphere. Intracerebralvessels constrict in response to cervical sympathetic stimulation anddilate when the nerve fibers are blocked. Ganglion blockade decreasedthe systolic blood pressure and cerebral blood flow in healthy humansubjects suggesting autonomic neural control of the cerebralcirculation. Cervical sympathetic ganglion or nerve block, at the levelof the superior cervical ganglion, of the ascending cervical sympatheticchain, using a local anesthetic agent (bupivacaine, clonidine and/orpropranolol) or an adrenergic blocker (norepinephrine, tyramine,phentolamine), has been shown to prevent worsening and reverseneurological symptoms in patients suffering from cerebral vasospasm.This technique may be used as a primary therapy or as an adjunct to thestandard therapy to improve cerebral perfusion and treat neurologicalsymptoms.

Increased or altered autonomic activity has also been cited as amechanism by which intracranial hemorrhage produces myocardial damageand cardiac arrhythmias. Atrial and ventricular arrhythmias and variousdegrees of A-V block were reported in patients suffering from SAH andanimals after intracranial hemorrhage. Thus, autonomic nerve blockade inpatients with intracranial hemorrhage may also be useful in preventingmyocardial damage and cardiac arrhythmias.

Methods are described to treat hemorrhagic stroke and resultant cardiacmedical conditions (arrhythmias, myocardial infarction, etc.) throughlocal chemical neuromodulation of the ANS, ganglia and nerve fibers ofsympathetic chain. A small volume (for example, approximately 0.01-20mL) of a drug may be administered at or near the cervical ganglia or thestellate ganglion to one or more of modulate, block, and ablate thenerves to vasodilate the cerebral arteries and increase blood flow andoxygen supply to the brain. The treatment may also be used to treatpatients that suffered a recent non-hemorrhagic stroke by increasingoxygen supply to the brain, through vasodilation and enhancedmicrocirculation within collateral channels, induced by ganglion ornerve blockade.

The drug may be administered using a needle under fluoroscopic (X-ray),CT, or ultrasound guidance to using the cervical vertebrae as landmarks.Formulations are described to achieve the desired nerve block degree andtreatment period. For example, the nerves may be blocked temporarily fora few hours, weeks or months. Nerves and nerve function may also bepermanently impaired preventing nerve regrowth and regeneration. Drugformulations, methods of administration, and visualization methods toachieve the above are described in detail in subsequent sections.

Pain—Trigeminal Neuralgia:

Trigeminal neuralgia (TN) is a neuropathic pain medical condition thataffects the trigeminal or fifth cranial nerve due to nerve injury ornerve lesion. Typically, Type 1 or TN1 is characterized by extreme,sporadic, burning or shock-like facial pain that lasts a few seconds totwo minutes per episode. Such episodes can occur in succession and lastup to two hours. Another form (Type 2 or TN2) is characterized byconstant aching and stabbing pain of lower intensity than Type 1. Bothpain forms may occur in the same person, sometimes at the same time, andthe intensity can be physically and mentally incapacitating.

The trigeminal nerve is one of twelve pairs of nerves that are attachedto the brain. The nerve has three branches that conduct sensations fromthe upper, middle, and lower portions of the face, as well as the oralcavity, to the brain. The ophthalmic, or upper, branch suppliessensation to most of the scalp, forehead, and front of the head. Themaxillary, or middle, branch stimulates the cheek, upper jaw, top lip,teeth and gums, and to the side of the nose. The mandibular, or lower,branch supplies nerves to the lower jaw, teeth and gums, and bottom lip.More than one nerve branch can be affected by this medical condition.

Current treatments for TN include oral anticonvulsant drugs(carbamazepine, oxcarbazepine, gabapentin etc.), tricyclicantidepressants (amitriptyline or nortriptyline). Common analgesics andopioids are not helpful. Medications are not always effective and canhave considerable side effects. Neurosurgical procedures (rhizotomy orrhizolysis) are also performed to damage the cranial nerve fibers andblock pain. Several forms of rhizotomy are available including ballooncompression (to squeeze a portion of the nerve against the hard edge ofthe brain and the skull), glycerol injection near the trigeminal nervecenter (or ganglion, the central part of the nerve from which the nerveimpulses are transmitted to the brain), radiofrequency thermal lesioning(heating the nerve using electrodes), stereotactic radiosurgery (usingGamma Knife, Cyber Knife focused beam of energy to create lesions on thenerve to disrupt the transmission of sensory signals) and microvasculardecompression (involving invasive surgery to move the artery or tissuecompressing the nerve by placing a soft cushion between the nerve andvessel). A partial resection of the nerve or neurectomy may also beperformed. Among these, microvascular decompression treatment surgery isthe most durable; about half of the patients are relieved of pain for12-15 years. All other treatments are effective for 1-3 years.Accordingly, there is a need for newer treatments that are less invasiveand more durable.

Methods are described to treat TN through neuromodulation. A smallvolume (for example, approximately 0.01-20 mL) of a drug may beadministered at or near one or more of the trigeminal nerve, stellateganglion, branches of the TN, and nerve fibers to one or more ofmodulate, block, and ablate the nerves and reduce sympathetic nerveoveractivity. A small volume of a drug formulation may be administeredat or near the stellate ganglion to cause a nerve block for a prolongedperiod, lasting a few days to several months or years to treat Bell'spalsy and other orofacial pain syndromes including neuropathic orofacialpain.

The drug may be administered using a needle under fluoroscopic (X-ray),CT, or ultrasound guidance. Formulations are described to achieve thedesired degree of nerve modulation over the treatment time period.Nerves and nerve function may also be permanently impaired preventingnerve regrowth and regeneration. Drug formulations, methods ofadministration, and visualization methods to achieve the above aredescribed in detail in subsequent sections.

Pain—Cancer, Chronic Pain and Post-Surgical Recovery Pain:

Most patients suffering from cancer experience pain. Acute and chronicpain can be nociceptive (mediated by mechanical, chemical, and thermalstimuli) or neuropathic (mediated by the dysfunction of nervous system).Nociceptive pain can be somatic pain or visceral pain. Somatic pain ismediated by the somatic nervous system, which innervates the skin, bone,and muscle, and is sharp, aching, or throbbing. Visceral pain ismediated by the ANS, which innervates internal structures such as thegastrointestinal tract, and is often difficult to localize or describeand sometimes characterized as crampy. Neuropathic pain can be eitherperipheral or central. The nerves may be damaged by ischemia,compression, infiltration, metabolic injury, or transection. Forexample, neuroma may be formed after thoracotomy due to aberrant healingafter surgery. Neuropathic pain may involve dysfunction of the nervoussystem. Repetitive nociceptive pain stimuli can cause increasedsensitivity of the spinal cord neurons (known as central facilitation)without structural damage to the nerves. Neuropathic pain tends to beassociated with burning, tingling, numbness, shooting, stabbing, orelectric-like feelings.

A three-step management of cancer pain based on World HealthOrganization (WHO) guidelines is in practice today. Patients with mildpain (Step 1, with a pain score of 1-3 on a 10-point numerical scale)are treated by aspirin, acetaminophen, non-steroidal anti-inflammatorydrugs (NSAIDs), and adjuvants. Adjuvants are co-administered to enhanceanalgesia and manage the adverse effects of drugs and opioids. Patientswith moderate pain (Step 2, with a pain score of 4-6) are treated byaspirin or acetaminophen, codeine, hydrocodone, oxycodone,dihydrocodeine, tramadol, and adjuvants. Patients with severe pain (Step3, with a pain score of 7-10) are treated by morphine, hydromorphine,methadone, levarphanol, fentanyl, oxycodone, non-opioid analgesics, andadjuvants. Drugs may be administered via oral, intravenous,intramuscular, enteral, subcutaneous, parenteral, or intraspinal routesto obtain desired pain relief. These pharmacological regimens havesignificant side effects causing patients, especially cancer patients,with significant discomfort and compromise in their quality of life.Constipation, dry mouth, nausea, vomiting, sedation, and sweats arecommon side effects; delirium, hallucinations, and urinary retention arerare but reported. Such limitations could be minimized by administeringa significantly small dose/volume of drug locally at or near targetnerve fibers associated with pain. Secondly, the continued use of opioidanalgesics for pain management following significant surgery, arthritis,migraines, and chronic back pain can lead to drug addiction, which is asignificant healthcare and social problem in the United States.

About 20-30% of cancer patients are refractory to pain medication orhave excessive side effects. An interventional approach to treating painis recommended by WHO for those patients. For example, the celiac plexusblock is commonly used to treat upper abdominal pain in patientssuffering from pancreatic cancer. The celiac plexus block involvesautonomic neural blockade of the sympathetic axis by infusing a localanesthetic agent like lidocaine or bupivacaine. This may be followed bythe superior hypogastric plexus block and the ganglion of impar blockfor patients with lower abdominal or pelvic pain. For patients withregional pain, a peripheral nerve block can be applied to any peripheralnerve, including the femoral, sciatic, paravertebral, brachial plexus,and interpleural nerves. For patients with severe pain, neural blocksare considered the primary mode of treatment.

Typically, the anesthetic drug is administered at the target nerve ortissue site inside the body, once or twice (as a bolus) and then, thenerve/tissue is continuously infused with drug for a few days to weeksusing a catheter. When longer infusions are needed, an implantable drugpump is used to provide pain relief. Current drugs have significant sideeffects and, in some cases, the treatments may not effective. Moreover,the catheters and implantable devices are inconvenient to cancer andterminally ill patients that suffer from severe pain. Thus, newtreatment methods and drug formulations are needed to manage and treatpain in cancer patients and patients recovering from complex surgery,that are safe and effective, to permanently block the target nerves andprovide durable pain relief without the inconvenience of intubateddevices or undesirable side effects from drug infusions.

Methods are described to treat chronic pain through neuromodulation. Asmall volume (for example, approximately 0.01-20 mL) of a drug may beadministered at or near the target nerve or tissue location to one ormore of modulate, block, and ablate the nerves and reduce sympatheticnerve overactivity. The drug formulation may be administered at or nearthe stellate ganglion to treat neuropathic pain syndromes in cancerpatients to achieve sustained pain block, over a period of days tomonths. The drug may be administered using a needle or a catheter underfluoroscopic (X-ray), CT, or ultrasound guidance. Formulations aredescribed to achieve the desired degree of extent of nerve modulationover the treatment time period. Nerves and nerve function may also bepermanently impaired preventing nerve regrowth and regeneration. Drugformulations, methods of administration, devices, and visualizationmethods to achieve the above are described in detail in subsequentsections.

Dermatology, Goiter and Fibromyalgia:

Goiter is a medical condition caused by enlargement of the thyroidgland, more commonly affecting women. In some cases, the goiter maydisappear on its own or become larger and may stop making thyroidhormone, a condition that is called hypothyroidism. In some cases, agoiter becomes toxic and produces thyroid hormone on its own increasinghormone levels, a condition referred to as hyperthyroidism. Fibromyalgiais a medical condition or disorder that causes widespread pain andfatigue. Stellate ganglion block using bupivacaine and guanethidine hasbeen used to treat fibromyalgia patients with mixed efficacy. Bilateralstellate-ganglion irradiation using xenon-light also showed animprovement in pain score immediately after treatment. Long-termdurability and potential damage to surrounding tissue are the majorlimitations; patients are expected to receive treatment at regularintervals.

Other Conditions—Hypertension, Etc.

Medical conditions like hypertension, chronic and vascularinsufficiency, and vascular disorder of the upper extremities such asRaynaud's disease, intra-arterial embolization, and vasospasm may betreated. Lymphatic drainage and edema of the upper extremity followingbreast surgery, post-herpetic neuralgia, phantom limb pain, andamputation stump pain may also be treated. Quinine poisoning, Meniere'sdisease (spontaneous episodes of vertigo, fluctuating hearing loss andfeeling of pressure or fullness in the ear), tinnitus (ringing in theear) and vascular headaches, like cluster and migraine headaches, mayalso be treated.

A small volume of a drug may be administered at or near the stellateganglion or ganglia of the sympathetic chain or nerves in between orportions of ganglia or nerves and nerve fibers to achieve nerve block ofsufficient duration. They may be effective for a day and longer-lastingthan an anesthetic without concomitant side effects. Such treatment maylast a few weeks, months, or years depending on the drug formulation anddrug release kinetics, as described in the following sections. A nerveblock may last between one to eight weeks. Examples of target medicalconditions and nerve target sites are listed in the Table 1 below.

TABLE 1 Treatment of Medical Conditions and Nerve Target Sites (One ormore sites) Medical Condition Target Nerve Locations Cardiac Atrialarrhythmias Stellate ganglion, ganglionated plexi, atrial myocardium,pulmonary veins, cardiac fat pads, rami communicantes Ventriculararrhythmias Stellate ganglion, cervical ganglion, ventricularmyocardium, dorsal thoracic nerve fibers, pericardial sac; ramicommunicantes Sudden cardiac death Stellate ganglion, C7-T2 sympatheticganglia; rami communicantes Myocardial infarction Stellate ganglion,cardiac substrate, C7-T2 sympathetic ganglia; rami communicantes; atrialor ventricular myocardium Angina Stellate ganglion, C7-T2 sympatheticganglia; rami communicantes; atrial or ventricular myocardium Heartfailure Stellate ganglion, C7-T2 sympathetic ganglia; ramicommunicantes; atrial or ventricular myocardium Cardiomyopathy Stellateganglion, C7-T2 sympathetic ganglia; rami communicantes; atrial orventral myocardium Chagas disease Stellate ganglion, C7-T2 sympatheticganglia; rami communicantes Channelopathies Long QT syndrome, CPVTStellate ganglion, C7-T2 sympathetic ganglia; rami communicantes Brugadasyndrome Stellate ganglion, C7-T2 sympathetic ganglia; ramicommunicantes Fibromyalgia Stellate ganglion, C7-T2 sympathetic ganglia;rami communicantes Short QT syndrome Stellate ganglion, C7-T2sympathetic ganglia; rami communicantes Tinnitus, Seizures Stellateganglion, C7-T2 sympathetic ganglia; rami communicantes Pain CRPSStellate ganglion, C7-T2 sympathetic ganglia; rami communicantes CancerNerves innervating the target tumor tissue Trigeminal neuralgia Stellateganglion, branches of trigeminal nerve Surgical pain Nerves affected bysurgery Chronic pain Nerves and nerve fibers near target pain locationsHot flashes Stellate ganglion, C7-T2 sympathetic ganglia; ramicommunicantes PTSD Stellate ganglion, C7-T2 sympathetic ganglia; ramicommunicantes Stroke Stellate ganglion, C7-T2 sympathetic ganglia; ramicommunicantes Other Goiter Stellate ganglion, C7-T2 sympathetic ganglia;rami communicantes Raynaud's disease Stellate ganglion, C7-T2sympathetic ganglia; rami communicantes Meniere's disease Stellateganglion, C7-T2 sympathetic ganglia; rami communicantes

Drug Neuromodulatory Effects: Mechanism of Action

Neuronal noise is a general term that is defined herein as randominfluences on the transmembrane voltage of single neurons, and byextension, the firing frequency of neural networks. This noise caninfluence the transmission and integration of signals from otherneurons, as well as, alter the firing activity of neurons in isolation.This noise can also affect innervated tissue homeostasis and generatedisturbances in cell signaling and physiology. Perturbation of neuronalnoise can lead to, or is associated with, disease states listed above.

Ion Pump and Ion Channel Antagonists:

Ion channels are ion-permeable pores in the lipid membranes of allcells. The channels open and close in response to stimuli, and thus gatethe flow of specific small ions. The ions flow downhillthermodynamically to enter or egress cells.

Ion pumps are non-ion permeable pumps in the lipid membranes of allcells that use chemical energy (in the form of adenosine triphosphate(ATP) hydrolysis) to power the transport of ions against anelectrochemical gradient (uphill, thermodynamically).

Both ion channels and ion pumps are highly abundant on cells in aganglion, as ion homeostasis (the regulation of ions that enablemaintenance of normal cellular responses) is a hallmark of a neuron.Indeed, the average charge difference across a neuronal membrane when atrest (−70 mV) differs significantly from the charge difference acrossthe membrane of an actively firing neuron (30 mV). The neuron utilizesboth ion channels and ion pumps for membrane depolarization (opening ofsodium channels) and repolarization (opening of potassium channels). TheNa+/K+ pump is responsible for maintaining the electrochemical gradientof the resting potential (−70 mV). Perturbations in its activity canlead to prolonged resting periods, cessation in neuronal firing (block)and/or death.

Conductance fluctuations in ion channels are driven by thermalfluctuations, and in some sense, amplify these fluctuations. Theseprotein channels are made up of subunits and complex domains that weavein and out of the cytoplasmic membrane, and undergo spontaneous changesin conformations between various open and closed states in aheat-influenced manner. The open state is characterized by a pore thatallows specific types of ionic species to migrate through the membrane,under the influence of an electrochemical driving force. Such a forcearises due to gradients in voltage and ionic concentration across theneural membrane. In a neuron where there are a large number of channels,single channel fluctuations have minimal impact on neuronal ionhomeostasis. When the number of channels is not large, single channelfluctuations can be described by a Markov process and can lead to actionpotentials (Strassberg and DeFelice, 1993). Similarly, in a neuron wherethere are a large number of channels, it requires multiple channels toundergo fluctuation to lead to action potentials.

The main component of the noise experienced by a neuron originates inthe myriad of synapses made by other cells onto it. Every spike arrivingat this synapse contributes a random amount of charge to the cell due tothe release noise. During the time a channel is open, ions migrate incomplex ways and varying amounts across the membrane. The associatedfluctuations are called channel shot noise. Continued perturbations maylead to downstream dysfunction within a neuron and downstream from saidneuron.

Discussed herein are drugs that may be used to regulate ion flow byagonistic or antagonistic interaction with ion channels or ion pumps toreduce shot noise, synaptic noise, or to regulate neuronal activity inthe ANS.

In some embodiments, it may be advantageous to contact a tissue with achannel blocker to affect ganglionic activity in the adjacent tissue. Inother embodiments, it may be advantageous to contact a tissue with anion pump antagonist to affect ganglionic activity in the adjacenttissue. Examples of channel blockers and ion pump antagonists for use inmodulating ANS activity in ganglionic cells, nerve fibers, ganglia, andnerve plexi include:

Na/K, H/K and Vacuolar ATPase Blockers:

Cardiac glycosides may be used to locally modulate the ANS. They inhibitNa(+)/K(+) ATPase, disrupt ion homeostasis, control aberrant ionhomeostasis, induce cell block or induce cytotoxicity in neurons.Cardiac glycosides may also regulate gene expression of MDR (Pgp), MRP(MRP1), CFTR or cAMP-activated Cl— channels, and other.3,4,5,6-Tetrahydroxyxanthone is another Na/K-ATPase inhibitor thatinhibits pump function without activating the kinase signaling function.It inhibits Na/K ATPase pump action with an affinity comparable toouabain, but does not alter sodium or ATP affinity, is not blocked bypotassium, and it does not activate the Src complex or downstreamkinases. Other examples of cardiac glycosides that may be used tolocally neuromodulate the ANS and related nerves include acetyldigoxin;G-strophanthin; digoxin; digitoxin; ouabain; ouabagenin; lanatoside C;proscillaridin; bufalin; oleandrin; deslanoside; marinobufagenin, andtheir variants.

SCH-28080 is a potent inhibitor of gastric H+ and K+-ATPase. Theantiulcer agents, SCH-28080 and SCH-32651 were examined for theirability to inhibit the H+K+ ATPase enzyme activity in a preparation ofmicrosomal membranes from rabbit fundic mucosa. SCH-28080 inhibited theisolated enzyme activity with a potency similar to omeprazole, IC50s of2.5 and 4.0 μM respectively. SCH 32651 was less potent exhibiting anIC50 of 200.0 μM. Both compounds may therefore exert their antisecretoryactivity via a direct inhibition of the parietal cell H+K+ ATPase.

Rabeprazole sodium is a gastric proton pump inhibitor. It suppresses theproduction of acid in the stomach by inhibiting the gastric H+/K+ ATPase(hydrogen-potassium adenosine triphosphatase) at the secretory surfaceof the gastric parietal cell. Rabeprazole sodium has been usedclinically to treat acid-reflux disorders (GERD), peptic ulcer disease,H. pylori eradication, and prevent gastrointestinal bleeds associatedwith NSAID use.

KM91104 is a cell-permeable vacuolar ATPase (V-ATPase) inhibitor thatspecifically targets the V-ATPase a3-B2 subunits interaction.Bafilomycin A1 is another specific inhibitor of V-ATPase. Both can beused in small volumes to locally neuromodulate the ANS and treat chronicmedical conditions.

Na/K, Na/H and Na/Ca Blockers:

Apamin, a potent Na/K channel blocker, and amiloride and its variantsare selective inhibitors of Na/H exchangers and may be used for localchemo neuromodulation of the ANS. The sodium-proton (Na/H) exchange is apredominant pathway for sodium to entry into an energy-deficient neuron,especially under ischemia-induced intracellular acidosis. The inhibitionof the Na/H pump by amiloride or its derivativeethyl-isopropyl-amiloride may be used to treat ANS dysfunction.

Cariporide is a selective inhibitor of the Na+/H+ exchanger subtype 1(NHE-1), also known as the Na+/H+ antiporter. Cariporide has shown tohave cardioprotective and antiarrhythmic effects, and has recently beeninvestigated for anticancer activity.

Zoniporide is a potent and selective inhibitor of Na+/H+ exchangerisoform 1 (NHE-1) with an IC50=59 nM at NHE-1, vs. 12,000 nM for NHE-2.It inhibits NHE-1-dependent Na+ uptake with an IC50 of 14 nM and hascardioprotective effects against myocardial injuries and ischemicinsults. It inhibits the swelling human platelets and attenuates cardiaccontractile dysfunction in rats. Zoniporide may have neurotoxic effectsas it causes peripheral sensory axonopathy.

KK4389KR is a Na+/H+ exchanger-1 (NHE-1) inhibitor (IC50=0.23 μM) thatmay treat ANS dysfunction. It inhibited NHE-1-mediated rabbit plateletswelling, and in anesthetized rats, reduced infarct size from 67%(control) to 43% (at 0.1 mg/kg) and 24% (at 1.0 mg/kg); reduced numberof ventricular premature beats from 530 to 266 (at 0.1 mg/kg) and 115(at 1.0 mg/kg); reduced VF incidence from 17 to 8 (0.1 mg/kg) and 0 (1.0mg/kg); with demonstrated efficacy for research and treatment ofmyocardial ischemic diseases in animal model. It may be used to modulateNHE-1 activity on NHE-1 expressing neurons.

CGP-37157 is a specific inhibitor of mitochondrial Na+/Ca2+ exchangerNCLX, as well as sarcoplasmic reticulum calcium-stimulated ATPase andpossibly other calcium channels to neuromodulate the ANS.3′,4′-dichlorobenzamil can be used to modulate ANS by inhibiting theNa+/Ca2+ exchanger, Na+ transport and sarcoplasmic reticulum Ca2+release channels. KB-R7943 (mesylate) is a reverse Na/Ca exchangerinhibitor that may treat ANS disorders.

Na, K, Ca Channel Blockers:

Prilocaine, novocaine, articaine, bupivacaine, and lidocaine blocksodium channels and are currently used for local nerve block and forspinal anesthesia. These drugs may be used in conjunction with the abovedrugs. They may also be mixed with polymers to construct drugformulations where the anesthetic effects last a few weeks to a fewyears. Methods and formulations are described in the following sections.

Other drugs to locally neuromodulate the ANS and treat medicalindications include QX-314 (chloride), a selective sodium channelblocker; glyburide, a potassium channel inhibitor shown to stimulateinsulin secretion; and mibefradil hydrochloride, used as a generalcalcium channel blocker.

Other TRPA, KCNQ and HCN Channel Blockers:

TRPA is a family of transient receptor potential ion channels and TRPA1is its sole member. It is expressed in the dorsal root ganglia andtrigeminal ganglion. A-967079 is a potent inhibitor of TRPA1, which maybe delivered locally at or near nerves and ganglia to modulate the ANS.

Humans have over 70 potassium channel genes, but only some are linked tomedical conditions. For example, mutations in the KCNQ family ofvoltage-gated potassium channels (KQT-like, subfamily Q) are associatedwith cardiac arrhythmias (long QT syndrome 1), deafness and epilepsy. XE991 is an inhibitor of KCNQ channels, and may be injected locally at ornear nerves or ganglia to treat ANS disorders.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels areproteins that serve as non-selective ligand-gated cation channels in theplasma membranes of heart and brain cells. HCN channels are also calledpacemaker channels because they help generate within the group ofneurons and cardiomyocytes. Zatebradine is a HCN channel blocker that isunder investigation for bradycardic activity. It may be deliveredlocally at or near neurons and ganglia to modulate autonomicdysfunction.

Voltage-Gated Channel Blockers:

Lamotrigine is a voltage-gated sodium channel inhibitor. Oxcarbazepineis an inhibitor of voltage gated sodium channels. Phenytoin blocksvoltage gated calcium channels and can be used as an anticonvulsant.Tetrodotoxin, saxitoxin, conotoxin, dendrotoxin, iberiotoxin, andheteropodatoxin are naturally occurring or synthetic and block sodium,voltage-gated sodium, or potassium channels. These drugs may be used tolocally neuromodulate nerves, ganglia, plexi, or a portion of a nerve totreat chronic medical conditions.

Na/Cl, K/Cl, Na/HCO3 Co-Transport Inhibitors:

The Na—K—Cl cotransporter (NKCC) is a protein that aids in the activetransport of sodium (Na), potassium (K), and chloride (Cl) ions acrossthe cell membrane. Two isoforms or this membrane transport protein,NKCC1 and NKCC2, are encoded. Bumetanide is an inhibitor of Na+/K+/Cl—co-transporter that can be used to treat ANS-mediated diseases. CLP257is a selective K+—Cl— co-transporter and KCC2 (Potassium chloridetransporter, a neuron-specific membrane protein expressed in the centralnervous system) activator that can be used to restore impaired Cl—transport in neurons with reduced KCC2 activity. Activating the KCC2transporter is a new mechanism for the treatment of neuropathic pain.Published evidence suggests that CLP257 can modulate plasmalemmal KCC2protein turnover post-translationally. KCC2 agonists may also be usedfor local neuromodulation, using methods described herein.

Torsemide is a loop diuretic of the pyridine-sulfonylurea class withanti-aldosteronergic properties and inhibitor of the Na+/K+/2Cl— carriersystem. It functions in the thick ascending limb of the loop of Henleand enhances the excretion of sodium, chloride and water from theluminal side of the cells. Furthermore, torsemide may treat oedematousconditions that are associated with diseases such as liver cirrhosis,kidney disorders and chronic congestive heart failure. It may be used tochemically neuromodulate the ANS.

VU0240551 is a potent, selective KCC2 inhibitor. KCC2 is apotassium-chloride exchanger expressed specifically in neurons. KCC2functions to lower intracellular chloride concentrations below theelectrochemical potential of the cells, thereby increasing thehyperexcitability of the neurons. KCC2 activity enhances GABA and otherinhibitory neurotransmission and is implicated in pain processing.VU0240551 was discovered in a high-throughput screen, followed bydirected medicinal chemistry. VU0240551 is selective for KCC2 over NKCC1(Na—K—Cl cotransporter). It binds competitively to the K+ site and bindsnoncompetitively to the Cl— site. It is the only small molecule withspecificity for a KCC family member.

Chlorthalidone is a thiazide-like diuretic, an inhibitor of the Na+-Cl—co-transporter. It inhibits Na+ ion transport across the renal tubularepithelium increasing the delivery of Na to the distal renal tubule andindirectly increasing potassium excretion via the Na—K exchangemechanism. Chlorthalidone also promotes Ca++ reabsorption by an unknownmechanism. Several recent comparison studies indicate thatchlorthalidone may be a better drug in preventing cardiovascular eventsthan hydrochlorothiazide. It may also be used to modulate GABA-mediatedneurotransmission, intracellular chloride concentration, andhypoexcitability or hyperexcitability. Chlorthalidone may also be usedto cause neuronal edema and cytolysis by local administration at or nearneurons.

S0859 is a selective high-affinity generic inhibitor of theNa+/HCO3-sodium bicarbonate co-transporter (NBC). S0859 does not inhibitNa+—H+ exchange (NHE). It may be a strong mediator of ANS when deliveredlocally at or near specific neurons and ganglia.

Other Drugs:

Concanamycin A may be used to inhibit acidification of organelles andperforin-mediated cytotoxicity. Sanguinarine is a benzophenanthridinealkaloid isolated from plants belonging to the family Papaveracea. Itexhibits anti-bacterial, anti-fungal, anti-inflammatory and anti-cancerproperties. It induces cell cycle arrest and sensitizes cancer cells toapoptosis by activating TNF-related apoptosis inducing ligand. Itinhibits STAT3, MMP-2, and MMP-9, interacts with glutathione, inducesgeneration of ROS, disrupts the microtubule assembly and causes DNAdamage resulting the death of the cancer cells. It may be used to affectnerve cells and modulate the ANS.

Stevioside is a noncaloric natural sweetener, 300 times more potent thansucrose. It inhibits transepithelial transport of p-aminohippurate (PAH)by interfering with the organic anion transport system. At 0.5-1 mM, itshowed no interaction with any organic anion transporters (OAT).Stevioside reportedly has genotoxic effects in cultured mammalian cells.

TGN-020 is an inhibitor of Aquaporin 4 (AQP4), the most abundant waterchannel in brain. Aquaporins (AQPs) are water channels required formaintaining fluid homeostasis and enabling water movement across barriermembranes, but can enhance pathological cellular volume changes andcause edema in injury states. Pretreatment with the AQP4 inhibitorTGN-020 significantly reduced the volume of brain edema associated withischemic injury in a mouse model of focal cerebral ischemia.

Xipamide is a sulfonamide diuretic that blocks sodium reabsorption inthe distal tubules of the kidney, resulting in increased urine output.Xiopamide also blocks the cystic fibrosis transmembrane conductanceregulator (CFTR) chloride channel. It may delivered locally at or nearneurons, ganglia, and nerve plexi to treat autonomic imbalance.

Drug formulation dose, concentration, and volume used for the localchemo neuromodulation of ganglionic cells, nerves, portions of nerves,plexi or ganglionated plexi by the antagonism of ion channels and ionpumps may vary based on drug half-life, proximity of target ganglia (andother neuronal sites of interest) from the site of administration,pharmacodynamics, and pharmacokinetics. In general, the total dose ofthe antagonist drug administered to a patient to modulate the gangliaand other target neuronal sites may be, for example, between 0.1nanograms and 15 milligrams. In other embodiments, the total doses ofthe ion- and pump-antagonist drugs may be, for example, in the range of10 nanograms and 30 micrograms.

Different drug formulations and doses may be delivered at or neardifferent target nerves based on their size, morphology, structure, andfunction. In general, higher drug doses can be delivered locally togenerate prolonged ganglionic cell-block or neurotoxicity. Specifically,higher doses may be needed to achieve the desired distribution of thedrug to affect cell soma and modulate the stellate ganglion. The totaldose of ion-channel or ion-pump antagonist drug delivered to a localtissue for ganglionic cytotoxicity may be, for example, between 0.001and 15 milligram dose. A smaller volume of drug and a different ordiluted concentration may be desirable to modulate individual nervefibers or axons innervating the ganglionated plexi within fat pads ofthe heart or the intrinsic cardiac nerves innervating the myocardium.

GPCR Agonists and Antagonists:

G-protein coupled receptors (GPCR) comprise a large superfamily ofreceptors typically sharing a common structural motif of seventransmembrane helical domains. Some GPCRs instead can be single-spanningtransmembrane receptors for cytokines such as erythropoeitin, epidermalgrowth factor (EGF), insulin, insulin-like growth factors I and II,transforming growth factor (TGF), or multi-polypeptide receptors such asGPIb-V-LX or the collagen receptor that exhibit outside-in-signaling viaG proteins. GPCRs play a vital role in the signaling processes thatcontrol cellular metabolism, cell growth and filamentation,inflammation, neuronal signaling, and blood coagulation. GPCRs also havea very important role as targets for molecules such as hormones,neurotransmitters and physiologically active substances, and act in amanner that controls, regulates, or adjusts the function of said GPCRsin a particular molecular and cellular context. For instance, GPCRsinclude receptors for biogenic amines, e.g., dopamine, epinephrine,histamine, glutamate, acetylcholine, and serotonin; for lipid mediatorsof inflammation such as prostaglandins, platelet activating factor, andleukotrienes; for peptide hormones such as calcitonin, C5aanaphylatoxin, follicle stimulating hormone, gonadotropin releasinghormone, neurokinin, oxytocin, and for proteases such as thrombin,trypsin, and factor VTIa/Xa; and for sensory signal mediators, e.g.,retinal photopigments and olfactory stimulatory molecules. In short,GPCRs are a major target for the modulation of ganglionic cell activityand ANS.

Unlike fast ligand-gated receptors, GPCRs are not ion channels. GPCRactions take 100 millisecond to minutes. Fast chemical synapses signalin a fraction of a millisecond. They always evoke complex pleiotropicresponses typically involving G proteins, second messengers, andnumerous intracellular targets. Fast chemical synaptic receptors onlychange the membrane potential and sometimes admit calcium ions into thecell. The GPCR coupled monoamines and peptides have longer extracellularlifetimes and thus cannot be targeted for point-to-point wiring to asingle postsynaptic cell in a circuit. They work on larger groups ofcells.

Common GPCR agonists that signal GPCRs located in ganglia are monoamineslike, adrenaline, noradrenaline, serotonin, dopamine, and histamine;small neurotransmitters like acetylcholine (mACh), gamma aminobutyricacid (GABAB), glutamate (metabotropic, mGluR), ATP (P2Y), adenosine, andcannabinoids; peptide neurotransmitters and hormones like opioids,somatostatin, NPY, oxytocin, vasopressin, neurotensins, VIP, galanin,kinins, releasing hormones, and many more; and sensory modalities likelight (rhodopsin), odorants, some tastetants including sweet, bitter,and umami.

For most of these GPCR agonists, there are multiple different sensitiveGPCRs. In some examples, one agonist can give rise to differentintracellular responses depending on the receptor subtypes and splicevariants expressed on ganglionic cells. For example, there are ninegenes encoding receptors for adrenaline and noradrenaline. Three of themcouple to the G-protein G_(q), often inducing intracellular calciumsignaling (al adrenergic receptors), three of them couple to G_(i),often inhibiting adenylyl cyclase activity, activating GIRK channels, orinhibiting calcium channel activity (α2 adrenergic receptors), and threeof them couple to G_(s), often stimulating adenylyl cyclase activity (βadrenergic receptors).

GPCR agonists are typically released at nerve terminals andvaricosities, these fast chemical synapses where presynaptic ACh,glutamate, GABA, or glycine release may activate post-synaptic receptorswithin nanometers of the release site, triggering the opening of ionchannels in one post-synaptic neuron within a fraction of a millisecond.Such agonist action stops in a few milliseconds because agonist isquickly removed from the synaptic cleft. GPCR signaling is fundamentallydifferent because GPCR agonists typically have a half-life of 200milliseconds to several minutes in tissue.

Importantly, agonist spread over such a time period can act on manycells. Thus, GPCR agonist spread beyond a single synapse (calledspillover) can have a distal effect. Agonists can thus be used to affectthe mode of operation of neural circuits in a paracrine, hormone-likemanner rather than providing specific modulatory effects on a singleneural bundle.

In some embodiments, GPCR agonist drugs may be administered locally ator near neurons and ganglia to up-regulate ganglionic cell activity.Agonist drugs that may be administered locally to target the GPCR onnerve tissue and modulate the ANS include: capsaicin; nicotine;glutamate; medroxyprogesterone acetate; genistein; acetylcholine;carbachol; suxamethonium; epibatidine; cytosine; nifene; varenicline;noradrenaline; amantadine; dextromethorphan; mecamylamine; memantine;methylcaconitine; phenylephrine; methoxamine; cirazoline;xylometazoline; midodrine; metaraminol; chloroethylchlonidine; agmatine;dexmedetomidine; medetomidine; romifidine; clonidine;chloroethylclonidine; brimonidine; detomidine; lofexidine; xylazine;tizanidine; guanfacine; amitraz; dobutamine; isoprenaline;noradrenaline; salbutamol; albuterol; bitolterol mesylate; formoterol;isoprenaline; levalbuterol; metaproterenol; salmeterol; terbutaline;ritadrine; L796568; amibegron; solabegron; mirabegron; and others.

In other embodiments, GPCR antagonist drugs may be administered todown-regulate ganglionic cell activity. Antagonist drugs that may beadministered at or near neural tissue to target the GPCR include:NPB112; MAb1; MAb23 monoclonal antibody; Nb6B9 nanobody; acepromazine;alfuzosin; doxazosin; phenoxybenzamine; phentolamine; prazosin;tamsulosin; terazosin; trazodone; amitriptyline; clomipramine; doxepin;trimipramine; hydroxyzine; yohimbine; idazoxan; atipamezole; metoprolol;atenolol; bisprolol; propranolol; timolol; nebivolol; vortioxetine;butoxamine; SR59230A; fasudil; guanfacine; chlonidine; scopolamine;trimethaphan camsylate; guanethidine; galantamine; pentolinium;pancuronium; bupropion; dextromethorphan; diphenidol; ibogaine;hexamethonium; mecamylamine; trimetaphan; conotoxin; bungarotoxin; MDMA;dihydro-beta-erythroidine; and others.

Other examples of drugs that may be administered in a local fashion forthe modulation of ganglionic cells via GPCR are listed in Drug Tables2-4.

TABLE 2 Drugs for local chemoneuromodulation Annual worldwide sales ofdrugs acting at GPCRs in the top 100 best selling prescription drugs in2000. Compound numbers refer to structures given in Scheme 1. TrademarkGeneric name Structure Company Disease Target receptor million $Claritin loratadine 1 Schering-Plough allergies H₁ antagonist 3 011  Zyprexa olanzapine 2 Eli Lilly schizophrenia mixed D₂/D₁/5-HT₂ 2 350  Cozaar losartan 3 Merck & Co hypertension AT₁ antagonist 1 715  Risperdal risperidone 4 Johnson & Johnson psychosis mixed D₂/5-HT_(2A) 1603   Leuplin/Lupron leuprolide 5 Takeda cancer LH-RH agonist 1 394  Neurontin gabapentin 6 Pfizer neurogenic pain GABA B agonist 1 334  Allegra/Telfast fexofenadine 7 Aventis allergies H₁ antagonist 1 070  Imigran/Imitex sumatriptan 8 GlaxoSmithKline migraine 5-HT₁ agonist 1068   Serevent salmeterol 9 GlaxoSmithKline asthma β₂ agonist 942 Plavixclapidogrel 10 Birstol-Myers Squibb stroke P2Y₁₂ antagonist 903 Zantacranitidine 11 GlaxoSmithKline ulcers H₂ antagonist 871 Singulairmontelukast 12 Merck & Co asthma LTD4 antagonist 860 Pepcidinefamotidine 13 Merck & Co ulcers H₂ antagonist 850 Cardura doxazosin 14Pfizer hypertension α₁ antagonist 795 Gaster famotidine 13 Yamanouchiulcers H₂ antagonist 763 Zofran ondansetron 15 GlaxoSmithKlineantiemetic 5-HT₃ antagonist 744 Zoladex goserelin 16 AstraZeneca cancerLH-RH antagonist 734 Diovan valsartan 17 Novartis hypertension AT₁antagonist 727 BuSpar buspirone 18 Bristol-Myers depression 5-HT₁antagonist 709 Zyrtec/Reactine cetirizine 19 Pfizer allergies H₁antagonist 699 Duragesic fentanyl 20 Johnson & Johnson pain opioidagonist 656 Atrovent ipratropium 21 Boehringer Ingelheim asthmaanticholinergic 598 Seloken metoprolol 22 AstraZeneca hypertension β₂antagonist 577

TABLE 3 Drugs for local chemoneuromodulation Receptor Target AntibodyCompany Disease Indication Status CCR4 KW-0761/AMG 761/ Kyowa HakkoKirin Cancer (adult T-cell leukemia) Approved in JP (Kyowa)Mogamulizumab CTCL Phase 3 Peripheral T and NK-cell lymphoma Phase 2PTCL Phase 2 Amgen Allergy Phase 1/2 (Amgen) AT008 Affitech CancerPreclinical CCR5 PRO140 CytoDyn Human immunodeficiency virus Phase 2completed HGS 1025 Human Genome Sciences/GSK Ulcerative colitisDiscontinued (Phase 1b) HGS 004 Human Genome Sciences/GSK HIV Phase 1completed Human Genome Sciences/GSK HIV Preclinical HGS 101 CrystalBioscience HIV Discovery Pepscan Undisclosed Discontinued (Discovery)(CCR5-2320) Tetravalent Roche HIV Preclinical bispecific CCR2 MLN1202Takeda-Millenium/South-West Bone metastatsis Phase 2 completed OncologyGroup MRCT/Univ Regensberg RA and MS Discovery C5aR NN-8209 G2Therapies/Novo Nordisk RA Phase 2 completed NN-8210 (back-up) SLE Phase1 terminated CGRP-R AMG-334 Amgen Migraine (prophylaxis) Phase 2 Hotflushes/menopause Phase 1 CXCR4 MDX-1338 (BMS936564)Medarex/Bristol-Myers Squibb B cell cancers (AML, CML, LBCL, FL) Phase 1ALX-0651 (nanobody) Ablynx Stem cell mobilization Discontinued (Phase 1)LY_2624587 Eli Lilly Cancer Discontinued (Phase 1) AT009 Affitech CancerPreclinical 515H7 Pierre Fabre Cancer/HIV Preclinical CX-02 & CX-05Northwest Biotherapeutics Cancer Preclinical GCG-R AMG477 Amgen Type 2diabetes Discontinued (Phase 1) Pepscan Undisclosed NDRR (Discovery)CXCR5 SAR113244 Sanofi RA/SLE Phase 1 CCR9 Takeda-Millenium Inflammation(Crohn's Disease) Discontinued (preclinical) VPAC-1 ThrombogenicsThrombocytopenia Discontinued (preclinical) FPRL Yes Biotech (Anogen)Alzheimer's disease NDRR (preclinical) BK2 DM-204 DiaMedica Type 2diabetes Preclinical CCR6 G2Therapies Inflammation Preclinical S1P3 7H9Expression Drug Designs Cancer Preclinical CXCR2 Crystal BioscienceCancer Discovery MorphoSys Cancer Discovery B2AR Crystal BioscienceRespiratory Discovery PAR1 Crystal Bioscience Cancer Discovery CXCR3AT0010 Affitech Inflammation Discovery S1P-R Pepscan Undisclosed NDRR(Discovery) CCR7 Pepscan Cancer, immunological disorders Discovery CXCR7Pepscan Cancer Discovery GLP-1R Abbott/HGS Type 1 or 2 diabetes NDRR(early stage) Neurological/metabolic CCR8 ICOS/Eli Lilly InflammationEarly stage (patent) C3aR Human Genome Sciences Asthma Early stage(patent) PAR2 Boehringer Ingelheim Inflammation (IBDS) Early stage(publication) Amgen Early stage (patent) LGR5 Kyowa Hakko Kirin CancerEarly stage (publication) CRTH2 Sosei/Abgenix Inflammation NDRR

TABLE 4 Drugs for local chemoneuromodulation GPR120 Agonist FFA1 pEC₅₀pEC₅₀ Selectivity and comments Reference EXAMPLE FFAs Palmitic acid(C16:0) 5.2-5.3 4.3 Several actions as nutrients and signalingmolecules. Briscoe et al. (2003), Itoh et Oleic acid (C18:1) 4.4-5.7 4.5Potency observed highly dependent on assay al. (2003), Hirasawa et al.DHA (C22:6) 5.4-6.0 5.4 constituents (e.g., BSA) (2005) PPARγ AGONISTSRosiglitazone 5.0-5.6^(a) N.D. GPR40 activity shared by related TZDssuch as Kotarsky et al. (2003), Hara troglitazone, ciglitazone, andpioglitazone. Low et al. (2009a), Smith et al. potency GPR120 agonismfor rosiglitazone (at (2009) 100 μM; Watson et al., unpublished) FFAR1AGONISTS MEDICA16 5.5.-5.9^(a) <5.0 Kotarsky et al. (2003, Hara et al.(2009b) GW9508 6.6-7.3 5.5 GPR40 activity 100-fold selective over apanel of 360 Briscoe et al. (2006), Smith other targets. pEC₅₀ valuesfor PPARα, δ, and γ were et al. (2009), Sum et al. 4.0, 4.0, and 4.9respectively (2007) Cpd B 7.1 N.D. Lead compound of series inactive atPPARs Tan et al. (2008), Zhou et al. Cpd C 6.8 (<10 μM). GPR40 knockoutabolished effects of Cpd (2010) B and C on insulin secretion in vivoTUG424 7.5^(b) N.D. No activity at FFA2 and FFA3 reported (TUG424).Christiansen et al. (2008), Cpd 37 7.1^(b) Cpd 37 has 100-foldselectivity for FFA1 over FFA2, Christiansen et al. (2011) FFA3, andPPARs, with improved pharmokinetic properties owing to reducedlipophilicity TAK-875 7.1^(c) N.D. Sasaki et al. (2011), Tsujihata etal. (2011) GPR120 AGONISTS Grifolic acid N.D. N.D. Weak GPR120 partialagonist without GPR40 activity Hara et al. (2009b) (at 100 μM) NCG21(Cpd 12) 4.7 5.9 Lacks PPARα, δ, and γ agonist activity (at 100 μM)Suzuki et al. (2008), Sun et al. (2010) Isoindolin-1-one series (Cpd 2)N.D. 6.7 Banyu patent Arakawa et al. (2010) Phenyl-isoxazol-3-ol series(Cpd 15) N.D. 7.2 Banyu patent Hashimoto et al. (2010) Metabolex (Cpd36) N.D. >6.0 Cpd 36 (100 mg/kg) reduced glucose excursion by Ma et al.(2010) 45% after an oral glucose tolerance test in lean C57BI/6J miceAgonist pEC₅₀ values quoted were obtained from fluorescent indicatormeasurements of Ca²⁺ mobilization, except ^(a)Smith et al. (2009)compared TZD agonism for FFA1 ERK activiation, while Kotarsky et al.(2003) measured FFA1 Ca²⁺ signaling using an aequorin reporter gene;^(b)measurement of insulin secretion/DMR assay; ^(c)measurement ofinositol phosphate accumulation. N.D.—not determined; pEC₅₀ values havenot been published.

Doses used for the modulation of ganglionic cells by agonism orantagonism of GPCRs may vary based on drug half-life, proximity oftarget ganglia from the site of administration (ganglia, plexus, nerve,axon, ganglionated plexus or fat pads), pharmacodynamics, andpharmacokinetics. In general, the total dose of GPCR agonist drugs maybe lower than the total dose of GPCR antagonist drug. Additionally, thetotal dose of drug targeting GPCR in a manner to induce neuronaltoxicity may be higher than the total dose of GPCR-targeted drug tostimulate or down-regulate neuronal activity. The total dose of GPCRdrug administered to a patient to modulate the autonomic ganglia may be,for example, between approximately 0.1 nanograms and approximately 30milligrams. In other embodiments, the total dose of GPCR agonist orantagonist drug administered may be, for example, between approximately10 nanograms and approximately 1 microgram.

In yet other embodiments, higher doses may be delivered locally, toachieve prolonged ganglionic cell block or cell death. In these cases,the total dose of GPCR-targeted drug may, for example, be betweenapproximately 0.01 and approximately 30 mg. In yet other embodiments,lower doses may be delivered locally by mixing the drug with a polymerand releasing the drug over a sustained period of time ranging between afew weeks to few months/years.

In yet other embodiments, different formulations may be delivered todifferent target sites. For example GPCR antagonist-based formulationsmay be delivered to the sympathetic ganglia regulating the SNS and GPCRagonist-based formulations may be delivered at or near the vagus PSNSsystem. In other embodiments, channel blockers may be delivered to theextrinsic sympathetic ganglia and GPCR based formulations may bedelivered to the intrinsic cardiac fibers innervating the heart.

Norepinephrine Transporter (NET) Inhibitors:

Norepinephrine transporter (NET) is protein that is responsible forreuptake of the extracellular NE and dopamine, especially in regulatingthe concentration of neurotransmitters in the synaptic cleft. NET anddopamine transporter (DAT) can transport NE and dopamine at the synapseand inside the neuronal cell. Different NET antagonists can inhibit NEreuptake through various mechanisms, when delivered locally, canmodulate the ANS and treat diseases. Drugs may include dihydropyridinecalcium antagonists (nifedipine, amlodipine), non-dihydropyridinecalcium antagonists (diltiazem, verapamil), uptake-1 inhibitors(alkaloid-cocaine, desipramine, fluoxedine, and opioid analgesics, liketramadol), antidepressants (trazodone, which acts by depletion ofneurosecretory vesicle content), sympathomimetics (pseudoephedrine), andmixed type inhibitors (a-b blockers, labetalol and reserpine).

Other Drug Classes:

Chemotherapeutic agents like doxorubicin, anthracyclines, paclitaxel,taxol, and cisplatin may be injected locally at or near nerves andganglia to neuromodulate and affect nerve function, organ function, andtreat various medical conditions. Injection of demyelinating agents(like lipocalin-2) and angiogenesis inhibitors (that specificallytargets proliferating endothelial cells, like, vasostatin) may also beused for local neuromodulation.

Drug Combinations

The formulations described may contain one or more drugs and otherconstituents for specific functions beyond excipients and buffers usedin pharmaceuticals to achieve the desired pH level, viscosity, andsolubility. These include compounds to improve the visibility of thedrug formulation during delivery to the target tissue under differentimaging conditions; and anesthetics to reduce local pain associated withnerve block and nerve damage during the procedure. Currently, in painblockade, a combination of local anesthetic, epinephrine, a steroid, andan opioid is often used to achieve temporary nerve block. Epinephrineconstricts blood vessels to slow the diffusion rate of the anesthetic,the steroid is used to reduce inflammation surrounding the overactiveganglionic cells, and the opioids block the pain. These embodiments maybe included into a drug formulation as an injectable for local injectionor into a polymer. Specific compounds and polymers are described in thefollowing sections.

In addition, two or more drugs may be used in combinatorial form todevelop a therapeutically efficacious drug formulation for localneuromodulation using individual drug component dose levels that aresafe and significantly below their local dose or concentration levelsrequired for neuromodulation. This mitigates the risk for toxicityassociated with potentially higher dose needed for local therapeuticneuromodulation. In one embodiment, patients may be pretreated withprecursor agents, either systemically or locally, to prepare the nerveof ganglion for neuromodulation. Pretreatment of the nerve with aprecursor drug formulation facilitates the local injection of a lowerdrug dose (volume or concentration) locally, to achieve prolongedganglionic cell block or cell death. This allows for the selective useof drugs and concentrations that are below their systemic toxicitylevels, yet be efficacious to locally neuromodulate and treat variousmedical conditions. One example of such combinatorial treatment is topretreat patients with parasympathomimetic and b-adrenolytic agents thatdiminish the toxicity of cardiac glycosides. For example, diazepam maybe administered as a precursor agent before local neuromodulation ofnerves and ganglia using cardiac glycosides and other ion channelblockers.

Drug Formulations

The active pharmaceutical ingredient (API) or bioactive molecule(s) ispresent in a therapeutically effective amount, i.e., an amountsufficient when administered locally to treat a disease or medicalcondition mediated thereby. The compositions may also include variousother agents to enhance delivery, safety, efficacy, and stability of theactive ingredients.

For example, the drug compositions may also include, depending on theformulation desired, pharmaceutically-acceptable, non-toxic carrierssuch as polyethylene glycol (PEG) or diluents, which are defined asvehicles commonly used to formulate pharmaceutical compositions foranimal or human administration. The diluent may be selected so as not toaffect the biological activity of the combination. Examples of suchdiluents include distilled water, buffered water, physiological saline,phosphate-buffered saline (PBS), Ringer's solution, dextrose solution,and Hank's solution. In addition, a pharmaceutical composition orformulation may include other carriers, adjuvants, or non-toxic,nontherapeutic, non-immunogenic stabilizers, excipients, and the like.Compositions may also include additional substances to approximatephysiological conditions, such as pH adjusting and buffering agents,toxicity adjusting agents, wetting agents, and detergents. Compositionsmay also include any of a variety of stabilizing agents, such as anantioxidant.

Further guidance regarding formulations that are suitable for varioustypes of administration can be found in Remington's PharmaceuticalSciences, Mace Publishing Company, Philadelphia, Pa., 17th ed. (1985).For a brief review of methods for drug delivery, see, Langer, Science249:1527-1533 (1990).

Pharmaceutical compositions may be administered for prophylactic and/ortherapeutic treatments. Toxicity and therapeutic efficacy of the activeingredient can be determined according to standard pharmaceuticalprocedures in cell cultures and/or experimental animals, including, forexample, determining the LD50 (the dose lethal to 50% of the population)and the ED50 (the dose therapeutically effective in 50% of thepopulation). The dose ratio between toxic and therapeutic effects is thetherapeutic index and it can be expressed as the ratio LD50/ED50.Compounds that exhibit large therapeutic indices may be used.

The data obtained from cell culture and/or animal studies can be used informulating a range of dosages for humans. The dosage of the activeingredient may lie within a range of circulating concentrations thatinclude the ED50 with little or no toxicity. The dosage may vary withinthis range depending upon the dosage form employed and the route ofadministration utilized.

To achieve local drug administration, a parenteral liquid formulationmay be generated by reconstituting lyophilized drug with solubilizer.Reconstituted drug and its formulation can be packaged in a vial,ampule, or prefilled syringe. Said liquid may include a solution,emulsion, or suspension. To generate said formulation, an effectiveamount of neuromodulatory drug may be formulated in the presence of oneor more of a solubilizer, stabilizer, buffer, tonicity modifier, bulkingagent, viscosity modifier, surfactant, chelating agent, and adjuvant.

In one embodiment, the drug may be formulated with a hydrophobic moiety.A hydrophobic moiety may include a lipid moiety or an amino acid. Ahydrophobic moiety may include: phospholipids, steroids, sphingosines,ceramides, octyl-glycine, 2-cyclohexylalanine, benzolylphenylalanine,propionoyl (C₃); butanoyl; pentanoyl (C₅); caproyl (C₆); heptanoyl (C₇);capryloyl (C₈); nonanoyl (C₉); capryl (C₁₀); undecanoyl (C₁₁); lauroyl(C₁₂); tridecanoyl (C₁₃); myristoyl; pentadecanoyl (C₁₅); palmitoyl(C₁₆); phtanoyl ((CH₃)₄); heptadecanoyl (C₁₇); stearoyl (C₁₈);nonadecanoyl (C₁₉); arachidoyl (C₂₀); heniecosanoyl (C₂₁); behenoyl(C₂₂); tracisanoyl (C₂₃); lignoceroyl (C2); alcohols; glycerol;polyethylene glycol; dimethylsulfoxide; mineral oil, and cholesterol;wherein said hydrophobic moiety is formulated in the presence of drug.

In another embodiment, the drug may be formulated with a salt. In yetanother embodiment, the drug may be formulated in the presence of anion. For example, anions of chloride; fluoride; or bromide may be used.Additionally, cations of calcium; potassium; sodium; or zinc may beused.

In yet another embodiment, the drug composition may include anontherapeutic compound (contrast agent) to assist with thevisualization of the drug injection to the target nerve tissue underdifferent body imaging conditions. Contrast agents that may be mixedinto the drug formulation for visibility under x-ray, electron-beam CT,external and intravascular ultrasound, and MRI are described insubsequent sections.

The components used to formulate the pharmaceutical compositions may beof high purity and may be substantially free of potentially harmfulcontaminants (e.g., at least National Food (NF) grade, generally atleast analytical grade, and more typically at least pharmaceuticalgrade). Moreover, compositions intended for in vivo use may be sterile.To the extent that a given compound must be synthesized prior to use,the resulting product may be substantially free of any potentially toxicagents, such as any endotoxins, which may be present during thesynthesis or purification process. Compositions for parentaladministration may also be sterile, substantially isotonic, and madeunder GMP conditions.

Sustained-Release Formulations

The above drug formulations may also be incorporated into a polymermatrix to release the drug over a period of time, ranging between a fewweeks to a few months/years, and affect the nerves and ANS function. Thepolymers may be biostable or biodegradable and constitute good matricesfor controlled drug delivery. Using different delivery methods anddevices, generally described in U.S. Pat. Nos. 6,923,986, 6,703,047,6,639,014, 6,632,457 and 6,514,534, different composite hydrogel-baseddrug formulations, gels, plugs, and microspheres containing thetherapeutic drug molecules described in the present invention may beadministered at or near the specific nerve target sites, sympatheticchain ganglia, and nerve fibers to treat disease by local chemicalneuromodulation.

The bioactive agent or therapeutic drug molecule is trapped in apolymeric network of hydrophobic regions which prevent the loss of thedrug. In some cases, the composite material has two phases, where bothphases are absorbable, but are not miscible. The continuous phase may bea hydrophilic network (such as a hydrogel, which may or may not becrosslinked) and the dispersed phase be hydrophobic (such as an oil,fat, fatty acid, wax or fluorocarbon, or other synthetic or waterimmiscible phase). In some cases, especially water soluble drugs, arelease rate modifying agent may also be used to incorporate the drugand control its release profile. Examples of macromers, polymers,cross-linkable groups, hydrophilic components and hydrophobic componentsand rate-releasing modifying agents are described below.

In one embodiment, biodegradable macromers are provided in an acceptablecarrier and crosslinking, covalently or non-covalently, to formhydrogels which are thermoresponsive. The drug formulations describedabove (biologically active drugs) may be incorporated in the macromersolution or in the resulting hydrogel after crosslinking. The hydrogelformulations are optimized for volume and drug release rate, which aretemperature dependent. The hydrogels may be formed in situ, for example,at a tissue site, and may be used for controlled release of drugs at ornear nerve tissue. The macromers used to form the hydrogels may also beoptimized for selective properties including hydrophobicity,hydrophilicity, thermosensitivity or biodegradability, and combinationsthereof. The gels permit controlled drug delivery and release the drugor biologically active agent in a predictable and controlled mannerlocally at the targeted nerve site.

The macromers may include cross-linkable groups which form covalentbonds with other compounds, while in aqueous solution. This allowscrosslinking of the macromers to form a gel, either after, orindependently from thermally dependent gellation of the macromer.Chemically or ionically crosslinkable groups known in the art may beprovided in the macromers. Polymerization chemistries may include, forexample, reaction of amines or alcohols with isocyanate orisothiocyanate, or of amines or thiols with aldehydes, epoxides,oxiranes, or cyclic imines; where either the amine or thiol, or theother reactant, or both, may be covalently attached to a macromer.Mixtures of covalent polymerization system, sulfonic acid, or carboxylicacid groups may be used.

The macromers may include hydrophobic domains and the hydrophobicity ofthe gel may be tailored to achieve a desired drug-release profile. Thecell membrane is composed of a lipid bilayer with the inner region beinghydrophobic. A hydrophobic tail may be incorporated into the macromer sothat the biologically active drug molecule can diffuse into the lipidbilayer. Examples of tail groups include fatty acids, diacylglycerols;molecules from membranes such as phosphatidylserine, and polycyclichydrocarbons and derivatives, such as cholesterol, cholic acid, steroidsand the like. In addition, more than one hydrophobic group may beincorporated into the macromer to improve adherence of the hydrogel tothe target tissue, the neuron. Examples of hydrophobic groups includeoligomers of hydroxy acids such as lactic acid or glycolic acid, oroligomers of caprolactone, amino acids, anhydrides, orthoesters,phosphazenes, phosphates, polyhydroxy acids or copolymers of thesesubunits. Also, the hydrophobic regions may be formed of poly(propyleneoxide), poly (butylene oxide), or a hydrophobic non-block mixed poly(alkylene oxide) or copolymers thereof. Poly L-lactide, or polyD,L-lactide or polyester, which is a copolymer of poly(lactic-coglycolic) acid (PLGA), may also be used.

The biodegradable macromers may also include hydrophilic regions byincorporating water-soluble hydrophilic oligomers available in the art.They may include polymer blocks of poly(ethylene glycol), poly(ethyleneoxide), poly(vinyl alcohol), poly(vinylpyrrolidone),poly(ethyloxazoline), or polysaccharides or carbohydrates such ashyaluronic acid, dextran, heparan sulfate, chondroitin sulfate, heparin,or alginate, or proteins such as gelatin, collagen, albumin, ovalbumin,or polyamino acids.

The biodegradable polymers incorporated into the formulation may behydrolyzable under in vivo conditions. Hydrolyzable groups includepolymers and oligomers of glycolide, lactide, epsilon-caprolactone, andother hydroxy acids. Poly(alpha-hydroxy acids) include poly(glycolicacid), poly(DL-lactic acid) and poly(L-lactic acid). Other materialsinclude poly (amino acids), polycarbonates, poly(anhydrides), poly(orthoesters), poly(phosphazines), and poly(phosphoesters). Polylactonessuch as poly(epsilon-caprolactone), poly(delta caprolactone),poly(delta-valerolactone) and poly(gamma butyrolactone). Monomeric,dimeric, trimeric, oligomeric, and polymeric regions may be used toyield a target polymer-drug formulation that is substantially watersoluble.

Release rate modifying agents may also be incorporated into drug-polymerformulations to control drug release. Hydrophobic agents are able toform a relatively stable dispersed phase within a continuous hydrogelmatrix and may be used as a secondary container for substantially watersoluble therapeutic drugs. A list of rate-release modifying agents maybe found in Table I of U.S. Pat. No. 6,633,457. Degradation times anddrug release profiles may be tailored by selecting appropriate polymersor monomers using linkages susceptible to biodegradation, such as ester,peptide, anhydride, and orthoester, phosphazine, and phosphoester bonds.Crystallinity and molecular weight may also significantly alterdegradation rates.

The hydrogel matrix may also include a biologically active agent, eithersingly or in combination with different agents. Examples of therapeuticor bioactive agents are described in previous sections.

Drug and/or drug-polymer formulations may also incorporate contrastagents to visualize the target site for delivery during the clinicalprocedure. Ionic contrast agents for visibility under x-ray fluoroscopyand CT include diatrizoate (Hypapaque) and metrizoate (Isopaque 370)monomers and ioxaglate (Hexbrix) dimer; non-ionic kind include iopamidol(Isovue 370), iohexol (Omnipaque 350), iopromide (Oxilan 350), iopromide(Ultravist 370), iodixanol (Visipaque 320) monomers, and ioversol dimer.Contrast agents for visibility under ultrasound include microbubbles ofsuphur hexafluoride (Sonovue, Bracco) and albumin shell withoctofluoropropane gas (Optison, GE heathcare) or lipid microspheres(Perflexane, Alliance Pharmaceutical; Perflutren). Barium sulphate mayalso be mixed into the formulation to improve the visibility of the drugformulation during injection to the target nerve site. For treatmentprocedures under MRI, contrast agents based on gadolinium likegadoterate (Dotarem), gadodiamide (Omniscan), gadobenate (MultiHance),gadopentetate (Magnevist), gadoteridol (ProHance), gadoversetamide(OptiMARK), gadobutrol (Gadavist), and gadopentetic acid dimeglumine(Magnetol) may be incorporated into the polymer and/or drug formulation.Many other gadolinium, iron-oxide, iron-platinum, manganese, andprotein-based contrast agents may also be incorporated into the drug ordrug-polymer formulations to improve the visibility of drug injectionunder MRI.

Drug and/or polymer formulations may also incorporate anesthetic agentsto reduce pain during the clinical procedure. Examples of ester-basedanesthetic agents that may be incorporated into the formulation includeprocaine, amethocaine, cocaine, benzocaine, and tetracaine. Examples ofamide-based are lidocaine, prilocaine, bupivicaine, levobupivacaine,ropivacaine, mepivacaine, dibucaine, and etidocaine. They may beincluded in the injectable (non-polymer) or polymer-based drugformulations.

Polymer-based drug formulations may be prepared outside the body insolid or gel form and delivered using different delivery systems to thetarget nerve locations. Ingredients or precursors of the formulationsmay be pre-packaged and sterilized, in dry or liquid forms, at amanufacturing facility. The dry or aqueous precursors may be premixed bymedical personnel in the clinical setting and injected at the targetnerve site. Water in the aqueous environment surrounding the targetnerve or ganglion initiates transformation and the formation of thedrug-releasing hydrogel implant. Alternatively, the finished product maybe mixed, sterilized, and packaged at a manufacturing facility or mixedby medical personnel.

Dry powder formulations may include a mixture of two or more individualdehydrated precursors and the drug formulation. The precursors activateupon exposure to water in bodily tissue, dissolve and simultaneouslycross link to form the hydrogel implant containing the drug formulation.In one embodiment, the precursors may comprise a lyophilized, orfreeze-dried forms that are compounded together with the drug. As anexample, a two-part dehydrated hydrogel precursor mixture may include anelectrophilic, multifunctional poly(ethylene glycol) (“PEG”) precursorand a multifunctional, nucleophilic PEG precursor. These two componentsmay be compounded together with the drug, when dry. Upon exposure to anaqueous environment, rapid chemical crosslinking occurs and forms adrug-releasing hydrogel implant. Another embodiment may include afully-synthetic, solid PEG particulate hydrogel composition. Adegradable PEG hydrogel is fabricated, then dried or lyophilized,pulverized, and mixed with the drug (biologically active ingredient)powder to form the hydrogel implant at or near the target nerve siteusing specific delivery systems.

Polymer-based drug formulations may also be prepared or cross-linkedinside the body to form the drug formulation described in this inventionusing different delivery systems. Two or more ingredient formulationsmay be prepared, packaged, and sterilized at a manufacturing facility(separate packages or a combined package with multiple chambers). Theymay be mixed using mixers, injecting guns, and delivery systems so thatthe polymers cross-link at the target nerves site location and releasethe drug over time.

In another embodiment, a hydrogel-based drug formulation product may befabricated in the anhydrous form and delivered to the target site insolid form. In situ swelling after the plug comes into contact withwater in the tissue initiates drug release to the target tissue.

Clinical Procedure and Devices

Agents described in the above sections may be injected locally, at ornear the target nerve sites in the body with a device, using differentimaging techniques such as x-ray (fluoroscopy or angiography), electronbeam computed tomography (EBCT or CT), magnetic resonance imaging (MRI),optical coherence tomography (OCT), external ultrasound or intravascularultrasound (IVUS) techniques. Imaging may be used to navigate a deviceto the target nerve site, visualize the nerves and tissue structuresurrounding the nerve, make necessary measurements about the nerveanatomy, orient the device, inject the drug locally, and delivertreatment. Imaging of organs and nerve stimulation may also be done toconfirm the nerve target nerves innervating organs and measure the nerveactivity before, during, and after treatment.

External Needle-Based Devices:

The device may include a syringe with a long 20-33 gauge needle to reachthe nerve site under X-ray, CT, MM, or ultrasound imaging. Variousapproaches may be used to puncture the skin and advance the needle toreach the stellate ganglion, other sympathetic chain ganglia and nerves.

One method may use a direct, anterior paratracheal approach to reach thetarget ganglion or nerve. A 5 cm long, 22 G needle may be insertedperpendicular to the skin (near the neck) until bone contact is made.The needle may be slightly withdrawn to rest anteriorly to theprecervical fascia to access the stellate ganglion. After a negativeaspiration test to verify that the location of the needle is (outsideblood vessels adjacent to the sympathetic ganglia, indicated by the lackof blood draw during aspiration, and) at or near the target ganglion,approximately 0.01 to 20 mL of the drug formulation may be injected.Other sympathetic chain ganglia, interconnecting nerve fibers, and ramicommunicantes may be similarly accessed and treated. The needle may beremoved and the access site closed.

A second method may use an anterior paratracheal approach to reach thetarget ganglion or nerve under external ultrasound guidance. The patientis placed in the supine posture and the neck region may be visualizedunder real-time ultrasound imaging using a 3-12 MHz linear array probe(HD11-XE® Philips, Washington, USA). A 5 cm long, 22 G needle may beinserted in the neck and then advanced to reach the stellate ganglion,so that the needle tip lays anterior to the longus coli muscle (anteriorto C6 transverse process). After a negative aspiration test to verifythat the needle is at the target nerve location, approximately 0.01 to20 mL of the drug formulation may be injected. Other sympathetic chainganglia, interconnecting nerve fibers, and rami communicantes may besimilarly accessed and treated.

A third method may use an anterior paratracheal approach to reach thetarget ganglion or nerve under external x-ray fluoroscopy guidance. Thepatient is positioned supine on a fluoroscopy table, placed intocervical extension with a shoulder roll and hemodynamically monitored(e.g., pulse oximetry, electrocardiogram). The patient is sedated orplaced under local anesthesia. The right C6 vertebral body isidentified, local anesthetic administered, and a 22-gauge needle may beadvanced percutaneously to the anterolateral C6 vertebral body. Theneedle location may be confirmed by x-ray and by negative aspiration toverify that no blood and cerebrospinal fluid is retrieved. A smallamount of contrast media may be injected through the needle to furtherconfirm needle location and assess the spread over the pre-vertebralplane. Digital subtraction angiography may be used to verify the absenceof vascular uptake. A small amount of local anesthetic may be injectedto further verify target site location. Then, approximately 0.01 to 20mL of the drug formulation, described below, may be injected gradually.The needle may be removed and the procedure is complete. Other nervetarget sites may be similarly accessed, including the cervical gangliaand thoracic ganglia of the sympathetic chain, ganglia, plexi, nerves,and portions of a nerve.

Other imaging methods like CT and MM imaging methods may similarly beused to treat the sympathetic chain ganglia and nerves. Currently mostneedles are made of metals and alloys like stainless steel andcobalt-chromium alloys. Metallic needles cause large imaging artifactsunder CT and MM imaging which makes it difficult to image and identifysurrounding tissue during the clinical procedure. Mill and CT compatibleneedles may be made from niobium, tantalum, platinum, zirconium, andpalladium-based alloys, which have low magnetic susceptibility, andproduce less artifacts and improve needle visibility during imaging.Other examples of non-metallic materials include ceramics, carbonfibers, polymers and their composites, etc. Metallic needle tip designsmay also be coated with bismuth and other low magnetic susceptibilitymaterials to clearly identify the target nerve tissue.

In one embodiment of the microneedle, one or more nanoelectrode sensorsmay be incorporated at the tip of the microneedle, on the surface, tomeasure the electrical signals transmitted from the target nerve,ganglion, or portion of the nerve. Sympathetic nerve activity may bemeasured directly using a wired connection to a datalogger or remotelyusing a wireless connection. For example, planar nanoelectrode arrays(PNAs) have been used to measure SNA near the stellate ganglion using awireless transmitter.

In another embodiment, the microneedle itself may be used to measure theSNA activity of the nerve, ganglion, or portion of the nerve. Typically,the microneedles are made of metals like stainless steel, high-carbonsteel. Further, they may be coated with high conductivity elements likegold, tungsten, tantalum and chromium to improve signal measurements.Typically, the peak nerve signals measurements from an exposed stellateganglion in dogs varied between 100-1500 microvolts. Such measurementsmay be used to study the efficacy of treatment by monitoring the signal,before, during, and after treatment, i.e., local administration of adrug formulation to modulate and/or interrupt nerve signaling.

Endoscope-Based Devices:

Another embodiment of a device may include an endoscope withcapabilities to visualize the target nerve and administer the drugformulation locally at the nerve target site, similar to a transthoracicendoscopic sympathectomy procedure. To treat the stellate ganglion, forexample, the patient may be placed under general anesthesia and about a6 mm incision may be made near the tip of the shoulder blade. Throughthis incision, a small endoscope, 5 mm in diameter, may be introducedinto the chest between the ribs. The lung may be retracted out of theway, and the sympathetic ganglia and nerves may be visualized with theendoscope. Through a second incision, a smaller device or instrument maybe introduced and advanced to the stellate ganglion under endoscopicguidance. The drug formulation may be gradually administered to thestellate ganglion. Both instruments may be removed and the treatment iscomplete.

Another endoscopic method to access the stellate ganglion, othersympathetic chain ganglia, and interconnecting nerves may use asupraclavicular approach. A small incision may be made above the leftclavicle, and the platysma and the clavicular head of thesternocleidomastoid muscle may be transected, avoiding injury to thethoracic duct. The scalene fat pad may be retracted laterally and theanterior scalene muscle (anterior to the carotid artery) and the phrenicnerve (anterior to the scalene muscle) may be identified. The phrenicnerve may be gently mobilized and the scalene muscle may be transectedand retracted upward to sufficiently expose the thoracic ganglia. Then,the seventh cervical transverse process (behind the subclavian artery)may be exposed along with the pleural dome, and the apical pleura may befreed from its ligament (Sibson's fascia). The lung may be deflectedcaudally to expose the stellate ganglion and the second thoracicganglion. A small volume of the drug formulation, described above, maybe injected locally at or near the stellate ganglion, other sympatheticchain ganglia, or interconnecting nerve fibers between the ganglia.Nerve activity at the stellate and sympathetic chain ganglia may bemonitored before and after local drug injection to verify the reductionin SNA and verify the acute efficacy of treatment using anelectrophysiology catheter or a high-frequency stimulation catheter.Once the treatment efficacy is verified, the lung may be repositioned,the muscles may be sutured, and the incision may be closed. No pleuraldrainage is needed because this approach does not require pleuralincision. Although the anatomical field of view is limiting with thesupraclavicular approach, the complications associated with pulmonary(pneumothorax), trauma, and aesthetics are reduced.

Yet another endoscopic method to access the sympathetic chain gangliaand interconnecting nerves between them may use a transaxillaryapproach. The upper arm may be abducted to about 100 degrees and thepectoralis major and intercostal muscles may be divided. The pleura maybe opened carefully avoiding the long thoracic nerve, the intercostalvessels, the azygos vein, and the thoracic duct. The lung may bedepressed to expose the posterior thoracic wall, the first rib may beidentified, and the pleura may be incised over the sympathetic trunk andthe appropriate ganglia or nerve fibers may be exposed. A small volumeof the drug formulation, described above, may be injected locally insideor adjacent to the stellate ganglion, other sympathetic ganglia, or theinterconnecting nerve fibers between them. Nerve activity inside thestellate and other ganglia may be monitored before and after local druginjection to verify the reduction in SNA and verify the acute efficacyof treatment. Once the treatment efficacy is verified, the lung may berepositioned, the different muscles may be sutured, and the incision maybe closed. This approach is a good alternative to open surgeryespecially in select patients and infants.

Other video assisted thoracic endoscopy procedures may be done throughthe chest (anterior and posterior) to reach the stellate ganglion andthe sympathetic chain ganglia. Other nerve target sites may be similarlyaccessed, including the cervical and thoracic ganglia of the sympatheticchain, ganglia, plexi, nerves, and portions of a nerve using endoscopytechniques. For example, two incisions on the fourth and fifthintercostal spaces may be used to reach and treat the second and thirdsympathetic ganglia and the interconnecting nerves between them.

The endoscopic procedures are less risky compared to open thoracotomywith reduced complication rates, and may need less pleural drainage timeand shorter hospital stays. The magnified surgical field of view andminimally invasive access (small scars in the axilla and the left chest)are the major advantages. However, there are limitations to theendoscopic approach. They include accidental hemorrhages, dedicatedinstrumentation and training, and incidence of pneumothorax (0.2-10%)and prolonged intercostal neuralgia (1-2%).

Catheter-Based Devices:

Another embodiment of the device may include an endovascular catheter,with multiple lumens, ports, and elements, to assist navigation throughthe vascular bed of the human body to the nerve target site and locallyadminister the drug. The catheter may be advanced from the venous orarterial blood circulation system. Typical endovascular access orpuncture sites for treatment include the femoral artery, femoral vein,brachial artery, brachial vein, radial artery, radial vein, carotidartery, carotid vein, subclavian artery, and subclavian vein. Cathetersmay be advanced from one of these puncture sites to reach one of theblood vessels adjacent to the target nerve location under X-rayfluoroscopy, CT, ultrasound, OCT, or MM guidance. The catheter may thenbe positioned in the vessel wall using an anchoring element andconfirmed using imaging. The injection element may then be activated andits location relative to the target nerve issue is verified underdifferent imaging conditions. After confirming the location, the drugformulation may be injected at or near the target nerve site. Aftertreatment, the injection element may be deactivated, the anchoringelement released, and the catheter removed from the body.

In one embodiment of the device, an anchoring element to stabilize theposition of the catheter may include a compliant balloon made from ahomogenous material. In other embodiments, the balloon may be made fromdifferent materials so that portions of the balloon are compliant toensure that the injection element is oriented towards the target nervelocation. In another embodiment, the balloon may incorporate anelectrical sensor (that accommodates balloon expansion) to locate thestellate or other sympathetic ganglion based on their localnerve-signaling activity. In yet another embodiment, the anchoringelement may include a spring or self-expanding mesh or stent-likestructure. The anchoring element may be constrained with a sheath of thecatheter. Once the catheter is advanced to the target nerve site, thesheath may be retracted so that the anchoring element is released toexpand and conform to the vessel wall. The self-expanding anchoringelement may be pre-shaped and constrained in such a way as to orient theinjection element towards the nerve target site upon release.

In one embodiment of the device, the injection element may include amicroneedle (or an equivalent drug delivery element). The injectionelement may be activated by the anchoring element (balloon expansion orunconstraining the self-expanding mesh) or activating it separatelyusing a handle to advance the microneedle across the vessel wall toreach the target nerve location. The microneedle may have sufficientstrength and caliber (for example, between approximately 10-200 micronsin diameter) to penetrate the vessel wall, yet small in diameter tominimize vessel trauma, vessel perforation, and bleeding complications.

In another embodiment, the injection component may include a needle-lesscomponent with a micro-aperture. The injection element may administer asmall volume (for example, approximately 10-500 microliters) of drugformulation to the target nerve tissue through a small aperture from areservoir by piercing the tissue under transient conditions (<1 second)of high pressure (between 100-10,000 psi). The method may comprisepositioning a delivery device including the aperture within the arteryand injecting the drug formulation at high velocity out of the aperture,across the artery wall. The drug acts on the local nerve tissue todisrupt nerve signal transmission and treat disease. The micro-aperturemay be of sufficient caliber (for example, between approximately 10-200microns in diameter) to avoid injury to the vessel wall (perforation,bleeding) and surrounding tissue. The needle-less component may be incommunication with the drug reservoir and the high-pressure injectionsystem on one end (outside the body) and the micro-aperture in contactwith the vessel wall (inside the body). The needle-less component mayinclude a balloon, a long injection tube, or a series of injectiontubes, with a micro-aperture in fluid communication with the drugreservoir.

The metallic injection elements (microneedles and hollow tubes) may beused as microelectrodes to monitor nerve signal activity before, during,and after treatment. In one embodiment, one or more nanoelectrodesensors may be incorporated on surfaces of the microneedle tips orinjection tubes to measure the electrical signals transmitted from thetarget nerve or ganglion. The Injection elements may be coated withgold, silver, carbon, tungsten, or other conductive coatings to monitorlocal ganglionic and nerve activity during the procedure. Both wired andwireless sensors may be used to monitor local nerve activity.

In another embodiment, the metallic injection elements (microneedles andhollow tubes) may be used to stimulate the cardiac nerves and measurethe extent of sympathetic nerve overactivity (stellate ganglion andother ganglia of the ECNS) or identify the regions of conductioninhomogeneity (in the myocardium). The microelectrodes may be connectedto a generator to stimulate the nerves and monitor nerve signal activitybefore, during, and after treatment. In one embodiment, one or morenanoelectrode sensors may be incorporated into the anchoring element toamplify the local nerve signal and assist measurement. Injection andanchoring elements incorporate additional sensors for activating andreceiving local nerve signals.

Delivery Systems for Injecting Polymer and Gel-Based Formulations:

The composition mixtures of the dehydrated hydrogel precursors and thedrug molecules may be delivered using several delivery systems that areknown in the medical and pharmaceutical art. They may be delivered usingpre-filled syringes or gas powered atomizers. Other delivery methodsinclude aerosolizing apparatus (Inhale Therapeutics, Aradigm Corp.) andpneumatic, needle-less injectors (Powderject Ltd., U.K.; Bioject,Portland, Oreg.). Pneumatic injectors may be actuated by compressedgases (argon, carbon dioxide, nitrogen, or helium), or springs. Theinjectors may be partially or fully disposable and often come packagedwith a fill needle or vial adaptor to draw the medication or animplant-forming material or solution from a vial into a syringe.

Methods of Access—ECNS:

Using a catheter, there are several endovascular navigation methods andendovascular locations for accessing different nerve target sites of theANS to treat various disease conditions, described above. In oneembodiment, the stellate ganglion may be accessed by introducing thecatheter through the femoral artery using standard endovascular methodsunder fluoroscopy. Typically, the methods involve using flexibleguidewires, guiding catheters, sheaths, and other ancillary devices toreach the vessel location. The catheter may then be advanced from thefemoral artery through the aorta and the subclavian artery and may bepositioned in any of the vessels adjacent to the stellate ganglion. Thecatheter may be positioned in the vessel or at the junction(intersection or bifurcation) between two vessels. As shown in FIGS.2A-2C, the vessel locations include the subclavian artery, the axillaryartery, the costocervical trunk, the deep cervical artery, the supremeor superior intercostal artery, the transverse cervical artery, thevertebral artery, the superficial cervical artery, the common carotidartery, the subclavian-vertebral artery ostium or bifurcation, etc. Anangiogram may be performed to confirm the position of the catheter. Amicroneedle may be activated to advance it across the vessel wall toreach the stellate ganglion. The position of the microneedle may beconfirmed through a test injection of contrast, and the drug formulationmay be gradually injected through the injection port of the catheter.The microneedle may be retracted and the catheter may be removed tocomplete the treatment procedure.

In another embodiment, the catheter may be introduced through thefemoral vein and advanced through the inferior venacava to reach thevenous circulation system adjacent to the stellate ganglion. These veinsinclude and are not limited to the subclavian vein, the axillary vein,the costocervical vein, the deep cervical vein, the supreme or superiorintercostal vein, the transverse cervical vein, the vertebral vein, thesuperficial cervical vein, the internal jugular vein, the externaljugular vein, the innominate vein etc., and the junction (bifurcation orintersection) etc. Catheters may be positioned in the veins on the leftvascular bed to access the left stellate ganglion and in the veins onthe right vascular bed to access the right stellate ganglion. The radialvein or brachial vein may be used to introduce the catheter in place ofthe femoral vein.

In another embodiment, the catheter may be introduced through the radialartery or brachial artery to reach the subclavian artery and the nearbyvasculature surrounding the cervical and thoracic ganglia, relatedsympathetic nerves, and nerve fibers shown in FIGS. 2A-2C. The radial orbrachial veins may be punctured to introduce and advance the catheter toreach the venous vasculature adjacent to target ganglia, sympatheticnerves, and nerve fibers.

In another embodiment, the catheter may be introduced through thevarious intercostal arteries or veins that run parallel to the ribs ofthe thoracic cavity to reach the cervical and thoracic ganglia, relatedsympathetic nerves, and nerve fibers, as shown in FIGS. 2A-2C. A smallincision may be made in the thoracic cavity to access the intercostalartery or vein to introduce and advance the catheter to reach the targetganglia, sympathetic nerves, and nerve fibers.

Endovascular devices and methods of vascular access for the treatment ofthe stellate ganglion and other ganglia of the sympathetic chaindescribed provide safety advantages over nerve block treatments usingneedle injections or video-assisted thoracic surgical procedures.Surgical trauma to the brachial plexus, trachea, esophagus, pleura, andthe lung, and related complications are avoided. Catheter-basedtreatment also reduces infections like local abscess, cellulitis, andosteitis. Voice loss and respiratory complications from paralysis of therecurrent laryngeal and phrenic nerves are also reduced through thedelivery of specific compositions and formulations (described below)that localize the drug effects to target neurons, plexi, and gangliawith minimal drug exposure and effects to surrounding tissue.

Other sympathetic chain ganglia may similarly be accessed through thethoracic vascular bed adjacent to the target nerve sites and treatedusing the procedures described above. For example, catheters may benavigated and positioned in the posterior intercostal artery or vein totreat the thoracic sympathetic chain ganglia, thoracic sympatheticnerves, and nerve fibers, as shown in FIGS. 2A-2C.

Methods of Access—ICNS:

In another embodiment, target nerve tissue in the myocardium, epicardialfat pads, and ganglionated plexi may be treated by chemo neuromodulationof the ICNS by injecting the drug formulations locally at or near theheterogeneous (arrhythmic myocardial) substrate regions of the heart.The catheter may be introduced under fluoroscopy through the femoral,brachial, or radial arteries and advanced to any of the arteriessupplying the heart and surrounding the heart (via the aorta) usingstandard endovascular or interventional techniques used bycardiologists, radiologists, and peripheral vascular physicians. Thecatheter may be positioned in the vessel or at the junction(intersection or bifurcation) between two vessels. Vessel locationsinclude the left anterior descending (LAD) artery and its branches, theright coronary artery (RCA) and its branches, the left circumflex artery(LCx) and its branches, and pulmonary veins and their bifurcations. Anangiogram may be performed to confirm the position of the catheter nearthe target site after the anchoring element is activated. The injectionelement may be activated and verified that it can administer drug intothe epicardial surface of the myocardium. A small volume of drugformulation may be injected to affect the intrinsic cardiac nerves inthe myocardium to treat the medical condition. High frequencystimulation (HFS) or similar electrophysiology (EP) mapping techniquesmay be used to identify the arrhythmic regions of the cardiac substratebefore and after treatment.

In another embodiment, the venous system may be used to access the heartat its vasculature for local neuromodulation of the ICNS. Catheters maybe introduced through the femoral, radial, or brachial vein to reach theheart through the venacava. The catheter may be positioned in the vesselor at the junction (intersection or bifurcation) between two vessels.The vessel locations include the great cardiac vein and its branches,the middle cardiac vein and its branches, the small cardiac vein and itsbranches, the anterior cardiac veins and its branches, coronary sinus,and pulmonary arteries and their bifurcations. An angiogram may beperformed to confirm the position of the catheter at the target nervesite after the anchoring element is activated. The injection element maybe activated and verified that it can administer drug into theepicardial surface of the myocardium. The drug formulation may beinjected locally at or near the intrinsic cardiac nerves in themyocardium to treat the medical condition.

Other vascular access sites (like, carotid artery or jugular vein, etc.)may also be used to introduce the catheter and advance it to the targetnerve site for treatment.

In another embodiment, the drug may be administered into the myocardiumfrom the endocardial surface of the heart. The catheter may be advancedinto the right or left atria or ventricles from the arterial or venousside. HFS and other EP mapping techniques may be used to identify thearrhythmic regions of the cardiac substrate. The catheter may bepositioned near the myocardial regions with heterogeneous innervationand the drug formulation may be injected locally to affect the intrinsiccardiac nerves and treat arrhythmias. HFS may be used to verify theefficacy of treatment and additional injections may be done tocompletely treat the disease.

In another embodiment, the drug may be administered to extrinsic andintrinsic cardiac nerves innervating the epicardial surface of theheart. Drug formulations may be injected into the pericardial sac toneuromodulate the cardiac nerves in the pericardium and the epicardium.Drugs may injected into the pericardium through any of the vascularmethods described above. Drug formulations may also be injected into thepericardium using non-vascular techniques, i.e., thoracoscopically (bymaking an incision between the ribs) using an endoscope

Surgical Access:

When minimally-invasive and endovascular methods to reach the stellateganglion or the sympathetic chain ganglia are not feasible, the targetnerve may be accessed directly through surgery and formulationsdescribed in the present invention may be injected locally. Openthoracotomy, including anterior transthoracic and axillary approaches,may be used to expose and treat the sympathetic chain. Thoracoscopicsympathectomy may also be used to treat the sympathetic chain ganglia.Minimally invasive surgical methods, using the supraclavicular and thetransaxillary approaches may also be used.

Methods of Clinical Diagnosis, Screening, and Treatment

Medical conditions described above have multiple pathological origins.Treatments, methods, devices and formulations are described to treatmedical conditions mediated by an overactive ANS. Also described aremethods to measure ANS activity and screen and qualify patients that canbenefit from the treatment. Also described are methods to monitor ANSactivity during and after treatment to monitor the efficacy oftreatment.

Direct measurement and stimulation of the target nerve signals may bedone using a needle with sensors or a microneedle element of a catheterused to inject a drug. They may be used to measure nerve signals duringand after drug injection to monitor the efficacy of treatment. Theneedles may be connected to electrical signal generators to stimulatethe nerves before, during, and after drug injection to monitor treatmentefficacy.

Other methods may be used to measure and monitor nerve signals before,during, and after treatment. These may include cardiac or otherorgan-related EKG/ECG changes on the skin, which may be monitored toverify the efficacy of local neuromodulation treatment. Changes in QRS,RR and QT interval, APD, EAD, ARI, and DAD may be monitored to test theefficacy of treatment. For example, stellate ganglion treatments maygenerate an increase in QT interval and decrease in RR interval and maybe detected using a 12-lead ECG.

Thoracic skin nerve activity (TSNA) may be used to estimate the nerveactivity of the stellate ganglion. The skin of the upper thorax isinnervated by sympathetic nerve fibers originating from the stellateganglion and is easily accessible. Changes in skin blood flow (using alaser Doppler flowmeter), skin temperature, and skin conductance(‘sympathogalvanic reflex’) may be measured with changes in ANS andstellate ganglion nerve activity. The rise in skin temperature in thehand (index finger) may be used to monitor treatment of the stellateganglion and other ganglia of the sympathetic chain. An increase anddifference in skin temperature of 1.5-2.0 degrees centigrade, betweenthe treated and untreated side, may be a good predictor forhyperhidrosis treatment.

Imaging and nerve stimulation and imaging may be used to verify theinnervated regions of the nerves, ganglia, and nerve fibers targeted fortreatment. They may also be used to verify the efficacy of treatment byimaging and/or stimulation after drug injection to the target site. Forexample, completeness of cardiac denervation may be confirmed at surgeryby direct electrical stimulation of the left and right ansae subclaviae(10 Hz, 5 msec, 5-7 V) and the left and right thoracic vagi (20 Hz, 5msec, 5-7 V). The absence of a change in heart rate and/or heart rhythmwith electrical stimulation of the cardiac nerves, at the time ofsurgery, confirms total denervation. Other techniques are describedbelow.

Baroreflex sensitivity (BRS) is a powerful tool for risk stratificationof patients before and after MI. The vagal parasympathetic nerve of thebaroreflex transports burst-like patterns to the heart, while thesympathetic limb inhibits the response. Baroreflex efferent nervesconnect to the sinoatrial node and control heart rate and heart ratevariability (HRV). Occurrence of VF is inversely related to BRS. A weakbaroflex causes frequent arrhythmias in patients and BRS<3milliseconds/mm Hg is a strong risk factor for sudden cardiac death. BRSis measured by changes in blood pressure and heart rate to intravenousinjection of phenylnephrine; vagal reflex is measured by lengthening ofthe RR interval. It can also be measured by blood pressure variation(BPV) from a continuous non-invasive finger arterial pressure (Finapressmethod). Variations of 0.1 Hz (0.04-0.15 Hz) are termed low frequencyand variability around 0.25 Hz (0.15-0.4 Hz) is termed high frequency(HF). Variations in HRV translate to variations in BPV. Blood pressurevariation can be continuously monitored before, during, and after druginjection to ensure that treatment is complete.

Autonomic sensitivity testing may also be used for monitoring and treatpatients. Heart rate testing at rest, during exercise (treadmilltesting), and recovery is a good marker of autonomic dysfunction andpredictor of sudden death. Chronotropic incompetence (<80% heart ratereserve), resting tachycardia (>100 beats/minute), and reduced heartrate recovery (at 1 minute <18 beats) are good predictors of long-termmortality, MI, or stroke in type 2 diabetes patients without knowncoronary artery disease. Heart rate variability (HRV) analysis based ona 10-minute ECG recording in a well-controlled environment is also agood measure of autonomic function. HRV, also measured as the ratio ofthe HF and LF spectral components can be used to monitor sympatheticnerve overactivity and autonomic dysfunction.

Autonomic GPs in the heart may be located by rapid atrial pacing using atemporary pacemaker or high frequency stimulation (HFS) to induce firingand map the ectopic nerve conduction sites in the heart. HFS isdelivered during the refractory period of the atrium and the PVs at afrequency of 20 Hz, amplitude of 20 volts, and pulse duration of 10milliseconds for 5 seconds per each site (BC-1100; Fukuda Denshi,Tokyo); or achieved at 1000 beats/minute (output of 18V and pulseduration of 0.75 milliseconds) by placing tweezers on the left-atrialepicardium. Target sites are considered for treatment when theydemonstrate a vagal reflex (prolonged RR interval and ventricularslowing) and a decrease of >20 mmHg in blood pressure.

Stimulation of the Sympathetic Ganglia and Ansae Subclaviae:

Stimulation of the left or right stellate ganglion or left or rightansae subclaviae may be performed to confirm the target nerve locationfor treatment. This may include placing the electrode or electrodeelement of the catheter at the nerve location, connecting it to anexternal stimulator, and measuring the cardiac EP activity in the heart.EKG, APD, EAD and DAD patterns may be analyzed to confirm the treatmentsite—unilateral, left or right, or bilateral. As noted above, othersympathetic chain ganglia between C7 to T5 may be involved. Theseganglia may be similarly accessed, stimulated, and EP measurements madeto confirm treatment location. The electrodes and electrode elements maybe used to monitor EP changes during and after local administration ofthe drug formulation to the target nerve site to confirm treatment.

MIBG:

Cardiac sympathetic denervation of the heart substrate and itsfunctionality may be assessed using 123-iodine metaiodobenzylguanidine(123-I MIBG) planar and single-photon emission computed tomography(SPECT) imaging. Heart to mediastinum ratios (H/M ratio) may be computedfor early and late planar imaging. MIBG-SPECT defect scores may becalculated by measuring tracer uptake within tissue. MIBG-SPECT defectscores were predictive of cardiac arrhythmic events in patientsindicated for ICD implantation. MIBG imaging also demonstrated thatmyocardial scarring and abnormalities in cardiac innervation werepredictive of cardiac mortality in HF patients, independent of leftventricular ejection fraction. Global cardiac sympathetic innervation,assessed using H/M ratio, was also found to be associated withappropriate ICD therapy.

Typically, the left and right stellate ganglia widely innervate theposterior and anterior ventricular walls of the heart, respectively. MIand hypertrophy induced nerve sprouting can innervate other regions. Themyocardium may be imaged using iodine-123 MIBG not only measure theextent of cardiac denervation and/or innervation but also locate thetarget regions of the heart that are innervated by the right or leftstellate ganglion. Once this determination is made, unilateral (left orright), or bilateral stellate ganglion treatment is performed.

Positron Emission Tomography (PET) may also be used to quantify theinhomogeneities in myocardial sympathetic innervation and used toidentify patients at highest risk for sudden cardiac arrest. PETimaging, assessed by 11C-meta-hydroxyephedrine (11C-HED), restingperfusion with 13N-ammonia and viability with 18F-2-deoxyglucose duringa hyperinsulinemic-euglycemic clamp, and predicted mortality from suddencardiac arrest independently of left-ventricular ejection fraction andinfarct volume in ischemic cardiomyopathy patients.

Magnetic resonance imaging (MRI) may also be used to identify patientsat risk for arrhythmias and sudden cardiac death. Late gadoliniumenhancement and the presence and extension of myocardial scarring atcardiac Mill were associated with life-threatening ventriculararrhythmia.

One or more of these methods can be used to diagnose patients withmedical conditions mediated by the ANS, treat the medical conditionsusing methods described, and verify the efficacy of treatment during orafter the procedure.

REFERENCES

-   1. M P Schlaich, E Lambert, D M Kaye, Z Krozowski, D J Campbell, G    Lambert, J Hastings, A Aggarwal and M D Esler, Sympathetic    Augmentation in Hypertension Role of Nerve Firing, Norepinephrine    Reuptake, and Angiotensin Neuromodulation, Hypertension, 2004; 43:    169-175.-   2. O A Ajijola, D Yagishita, N K Reddy, K Yamakawa, M Vaseghi, A M    Downs, D B Hoover, J L Ardell and K Shivkumar, Remodeling of    stellate ganglion neurons after spatially targeted myocardial    infarction: neuropeptide and morphologic changes, Heart Rhythm,    2015; 12(5), 1027-1035.-   3. SF Fernandez and J M Canty Jr., Adrenergic and Cholinergic    Plasticity in Heart Failure, Circulation Research, 2015; 116:    1639-1642.-   4. K Fukuda, H Kanazawa, Y Aizawa, J L Ardell and K Shivkumar,    Cardiac Innervation and Sudden Cardiac Death, Circulation Research,    2015; 116: 2005-2019.-   5. C M Ripplinger, S F Noujaim, D Linz, The nervous heart, Progress    in iophysics and Molecular Biology, 2016; xx: 1-11.-   6. M J Shen and DP Zipes, Role of the Autonomic Nervous System in    Modulating Cardiac Arrhythmias, Circulation Research, 2014; 114:    1004-1021.-   7. O A Ajijola, N Lellouche, T Bourke, R Tung, S Ahn, A Mahajan and    K Shivkumar, MD PhD*, †Bilateral cardiac sympathetic denervation for    the management of electrical storm, JACC, 2012; 59(1): 91-92.-   8. M. Vaseghi, J Gima, C Kanaan, O A Ajijola, A Marmureanu, A    Mahajan and K Shivkumar, Cardiac sympathetic denervation in patients    with refractory ventricular arrhythmias or electrical storm:    Intermediate and long-term follow-up, Heart Rhythm, 2014; 11:    360-366.-   9. P Schwartz, M Motolese, G Pollavini, A Lotto, U Ruberti, R    Trazzi, C Bartorelli, A Zanchetti and the Italian Sudden Death    Group, Prevention of Sudden Cardiac Death After a First Myocardial    Infarction by Pharmacologic or Surgical Antiadrenergic    Interventions, J. Cardiovasc Electrophysiol, 1992; 3: 2-16.-   10. C A Collura, J N Johnson, C Moir and M J Ackerman, Left cardiac    sympathetic denervation for the treatment of long QT syndrome and    catecholaminergic polymorphic ventricular tachycardia using    video-assisted thoracic surgery, Heart Rhythm, 2009; 6: 752-59.

What is claimed is:
 1. A method for treating a disease condition of thesympathetic nervous system in a patient, the method comprising:delivering an agent locally to a stellate ganglion of the patient in anamount sufficient to affect function of the stellate ganglion andalleviate one or more symptoms of the disease condition in the patient.2. A method for treating a disease condition of the autonomic nervoussystem in a patient, the method comprising: delivering an agent locallyto a stellate ganglion of the patient in an amount sufficient to affectfunction of the stellate ganglion and alleviate one or more symptoms ofthe disease condition in the patient.
 3. A method for treating a diseasecondition of the peripheral nervous system in a patient, the methodcomprising: delivering an agent locally to a stellate ganglion of thepatient in an amount sufficient to affect function of the stellateganglion and alleviate one or more symptoms of the disease condition inthe patient.
 4. A method for treating cardiac disease in a patient, themethod comprising: delivering a cardiac glycoside locally to a stellateganglion of the patient in an amount sufficient to affect function ofthe stellate ganglion and affect one or more symptoms of cardiac diseasein the patient.
 5. A method for treating cardiac disease in a patient,the method comprising: delivering a cardiac glycoside locally to a leftstellate ganglion of the patient in an amount sufficient to affectfunction of the left stellate ganglion and affect one or more symptomsof cardiac disease in the patient.
 6. The use of an agent for themanufacture of a medicament for the treatment of a disease condition ofthe sympathetic nervous system by local delivery to a stellate ganglion.7. The use of an agent for the manufacture of a medicament for thetreatment of a disease condition of the autonomic nervous system bylocal delivery to a stellate ganglion.
 8. The use of an agent for themanufacture of a medicament for the treatment of a disease condition ofthe peripheral nervous system by local delivery to a stellate ganglion.9. The use of a cardiac glycoside for the manufacture of a medicamentfor the treatment of cardiac disease by local delivery to the stellateganglion.
 10. The use of a cardiac glycoside for the manufacture of amedicament for the treatment of cardiac disease by local delivery to theleft stellate ganglion.